Category Archives: Genetics

This article is about the general scientific term. For the scientific journal, see Genetics (journal).

Genetics is the study of genes, genetic variation, and heredity in living organisms.[1][2] It is generally considered a field of biology, but it intersects frequently with many of the life sciences and is strongly linked with the study of information systems.

The father of genetics is Gregor Mendel, a late 19th-century scientist and Augustinian friar. Mendel studied 'trait inheritance', patterns in the way traits were handed down from parents to offspring. He observed that organisms (pea plants) inherit traits by way of discrete "units of inheritance". This term, still used today, is a somewhat ambiguous definition of what is referred to as a gene.

Trait inheritance and molecular inheritance mechanisms of genes are still primary principles of genetics in the 21st century, but modern genetics has expanded beyond inheritance to studying the function and behavior of genes. Gene structure and function, variation, and distribution are studied within the context of the cell, the organism (e.g. dominance) and within the context of a population. Genetics has given rise to a number of sub-fields including epigenetics and population genetics. Organisms studied within the broad field span the domain of life, including bacteria, plants, animals, and humans.

Genetic processes work in combination with an organism's environment and experiences to influence development and behavior, often referred to as nature versus nurture. The intra- or extra-cellular environment of a cell or organism may switch gene transcription on or off. A classic example is two seeds of genetically identical corn, one placed in a temperate climate and one in an arid climate. While the average height of the two corn stalks may be genetically determined to be equal, the one in the arid climate only grows to half the height of the one in the temperate climate due to lack of water and nutrients in its environment.

The word genetics stems from the Ancient Greek genetikos meaning "genitive"/"generative", which in turn derives from genesis meaning "origin".[3][4][5]

The observation that living things inherit traits from their parents has been used since prehistoric times to improve crop plants and animals through selective breeding.[6] The modern science of genetics, seeking to understand this process, began with the work of Gregor Mendel in the mid-19th century.[7]

Prior to Mendel, Imre Festetics, a Hungarian noble, who lived in Kszeg before Mendel, was the first who used the word "genetics". He described several rules of genetic inheritance in his work The genetic law of the Nature (Die genetische Gestze der Natur, 1819). His second law is the same as what Mendel published. In his third law, he developed the basic principles of mutation (he can be considered a forerunner of Hugo de Vries.)[8]

Other theories of inheritance preceded his work. A popular theory during Mendel's time was the concept of blending inheritance: the idea that individuals inherit a smooth blend of traits from their parents.[9] Mendel's work provided examples where traits were definitely not blended after hybridization, showing that traits are produced by combinations of distinct genes rather than a continuous blend. Blending of traits in the progeny is now explained by the action of multiple genes with quantitative effects. Another theory that had some support at that time was the inheritance of acquired characteristics: the belief that individuals inherit traits strengthened by their parents. This theory (commonly associated with Jean-Baptiste Lamarck) is now known to be wrongthe experiences of individuals do not affect the genes they pass to their children,[10] although evidence in the field of epigenetics has revived some aspects of Lamarck's theory.[11] Other theories included the pangenesis of Charles Darwin (which had both acquired and inherited aspects) and Francis Galton's reformulation of pangenesis as both particulate and inherited.[12]

Modern genetics started with Gregor Johann Mendel, a scientist and Augustinian friar who studied the nature of inheritance in plants. In his paper "Versuche ber Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Naturforschender Verein (Society for Research in Nature) in Brnn, Mendel traced the inheritance patterns of certain traits in pea plants and described them mathematically.[13] Although this pattern of inheritance could only be observed for a few traits, Mendel's work suggested that heredity was particulate, not acquired, and that the inheritance patterns of many traits could be explained through simple rules and ratios.

The importance of Mendel's work did not gain wide understanding until the 1890s, after his death, when other scientists working on similar problems re-discovered his research. William Bateson, a proponent of Mendel's work, coined the word genetics in 1905.[14][15] (The adjective genetic, derived from the Greek word genesis, "origin", predates the noun and was first used in a biological sense in 1860.)[16] Bateson both acted as a mentor and was aided significantly by the work of women scientists from Newnham College at Cambridge, specifically the work of Becky Saunders, Nora Darwin Barlow, and Muriel Wheldale Onslow.[17] Bateson popularized the usage of the word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.[18]

After the rediscovery of Mendel's work, scientists tried to determine which molecules in the cell were responsible for inheritance. In 1911, Thomas Hunt Morgan argued that genes are on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies.[19] In 1913, his student Alfred Sturtevant used the phenomenon of genetic linkage to show that genes are arranged linearly on the chromosome.[20]

Although genes were known to exist on chromosomes, chromosomes are composed of both protein and DNA, and scientists did not know which of the two is responsible for inheritance. In 1928, Frederick Griffith discovered the phenomenon of transformation (see Griffith's experiment): dead bacteria could transfer genetic material to "transform" other still-living bacteria. Sixteen years later, in 1944, the AveryMacLeodMcCarty experiment identified DNA as the molecule responsible for transformation.[21] The role of the nucleus as the repository of genetic information in eukaryotes had been established by Hmmerling in 1943 in his work on the single celled alga Acetabularia.[22] The HersheyChase experiment in 1952 confirmed that DNA (rather than protein) is the genetic material of the viruses that infect bacteria, providing further evidence that DNA is the molecule responsible for inheritance.[23]

James Watson and Francis Crick determined the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin and Maurice Wilkins that indicated DNA had a helical structure (i.e., shaped like a corkscrew).[24][25] Their double-helix model had two strands of DNA with the nucleotides pointing inward, each matching a complementary nucleotide on the other strand to form what looks like rungs on a twisted ladder.[26] This structure showed that genetic information exists in the sequence of nucleotides on each strand of DNA. The structure also suggested a simple method for replication: if the strands are separated, new partner strands can be reconstructed for each based on the sequence of the old strand. This property is what gives DNA its semi-conservative nature where one strand of new DNA is from an original parent strand.[27]

Although the structure of DNA showed how inheritance works, it was still not known how DNA influences the behavior of cells. In the following years, scientists tried to understand how DNA controls the process of protein production.[28] It was discovered that the cell uses DNA as a template to create matching messenger RNA, molecules with nucleotides very similar to DNA. The nucleotide sequence of a messenger RNA is used to create an amino acid sequence in protein; this translation between nucleotide sequences and amino acid sequences is known as the genetic code.[29]

With the newfound molecular understanding of inheritance came an explosion of research.[30] A notable theory arose from Tomoko Ohta in 1973 with her amendment to the neutral theory of molecular evolution through publishing the nearly neutral theory of molecular evolution. In this theory, Ohta stressed the importance of natural selection and the environment to the rate at which genetic evolution occurs.[31] One important development was chain-termination DNA sequencing in 1977 by Frederick Sanger. This technology allows scientists to read the nucleotide sequence of a DNA molecule.[32] In 1983, Kary Banks Mullis developed the polymerase chain reaction, providing a quick way to isolate and amplify a specific section of DNA from a mixture.[33] The efforts of the Human Genome Project, Department of Energy, NIH, and parallel private efforts by Celera Genomics led to the sequencing of the human genome in 2003.[34]

At its most fundamental level, inheritance in organisms occurs by passing discrete heritable units, called genes, from parents to progeny.[35] This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants.[13][36] In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or whitebut never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.

In the case of the pea, which is a diploid species, each individual plant has two copies of each gene, one copy inherited from each parent.[37] Many species, including humans, have this pattern of inheritance. Diploid organisms with two copies of the same allele of a given gene are called homozygous at that gene locus, while organisms with two different alleles of a given gene are called heterozygous.

The set of alleles for a given organism is called its genotype, while the observable traits of the organism are called its phenotype. When organisms are heterozygous at a gene, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.[38]

When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.

Geneticists use diagrams and symbols to describe inheritance. A gene is represented by one or a few letters. Often a "+" symbol is used to mark the usual, non-mutant allele for a gene.[39]

In fertilization and breeding experiments (and especially when discussing Mendel's laws) the parents are referred to as the "P" generation and the offspring as the "F1" (first filial) generation. When the F1 offspring mate with each other, the offspring are called the "F2" (second filial) generation. One of the common diagrams used to predict the result of cross-breeding is the Punnett square.

When studying human genetic diseases, geneticists often use pedigree charts to represent the inheritance of traits.[40] These charts map the inheritance of a trait in a family tree.

Organisms have thousands of genes, and in sexually reproducing organisms these genes generally assort independently of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "Law of independent assortment", means that the alleles of different genes get shuffled between parents to form offspring with many different combinations. (Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)

Often different genes can interact in a way that influences the same trait. In the Blue-eyed Mary (Omphalodes verna), for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all or are white. When a plant has two copies of this white allele, its flowers are whiteregardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first.[41]

Many traits are not discrete features (e.g. purple or white flowers) but are instead continuous features (e.g. human height and skin color). These complex traits are products of many genes.[42] The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability.[43] Measurement of the heritability of a trait is relativein a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a trait with complex causes. It has a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.[44]

The molecular basis for genes is deoxyribonucleic acid (DNA). DNA is composed of a chain of nucleotides, of which there are four types: adenine (A), cytosine (C), guanine (G), and thymine (T). Genetic information exists in the sequence of these nucleotides, and genes exist as stretches of sequence along the DNA chain.[45]Viruses are the only exception to this rulesometimes viruses use the very similar molecule, RNA, instead of DNA as their genetic material.[46] Viruses cannot reproduce without a host and are unaffected by many genetic processes, so tend not to be considered living organisms.

DNA normally exists as a double-stranded molecule, coiled into the shape of a double helix. Each nucleotide in DNA preferentially pairs with its partner nucleotide on the opposite strand: A pairs with T, and C pairs with G. Thus, in its two-stranded form, each strand effectively contains all necessary information, redundant with its partner strand. This structure of DNA is the physical basis for inheritance: DNA replication duplicates the genetic information by splitting the strands and using each strand as a template for synthesis of a new partner strand.[47]

Genes are arranged linearly along long chains of DNA base-pair sequences. In bacteria, each cell usually contains a single circular genophore, while eukaryotic organisms (such as plants and animals) have their DNA arranged in multiple linear chromosomes. These DNA strands are often extremely long; the largest human chromosome, for example, is about 247 million base pairs in length.[48] The DNA of a chromosome is associated with structural proteins that organize, compact and control access to the DNA, forming a material called chromatin; in eukaryotes, chromatin is usually composed of nucleosomes, segments of DNA wound around cores of histone proteins.[49] The full set of hereditary material in an organism (usually the combined DNA sequences of all chromosomes) is called the genome.

While haploid organisms have only one copy of each chromosome, most animals and many plants are diploid, containing two of each chromosome and thus two copies of every gene.[37] The two alleles for a gene are located on identical loci of the two homologous chromosomes, each allele inherited from a different parent.

Many species have so-called sex chromosomes that determine the gender of each organism.[50] In humans and many other animals, the Y chromosome contains the gene that triggers the development of the specifically male characteristics. In evolution, this chromosome has lost most of its content and also most of its genes, while the X chromosome is similar to the other chromosomes and contains many genes. The X and Y chromosomes form a strongly heterogeneous pair.

When cells divide, their full genome is copied and each daughter cell inherits one copy. This process, called mitosis, is the simplest form of reproduction and is the basis for asexual reproduction. Asexual reproduction can also occur in multicellular organisms, producing offspring that inherit their genome from a single parent. Offspring that are genetically identical to their parents are called clones.

Eukaryotic organisms often use sexual reproduction to generate offspring that contain a mixture of genetic material inherited from two different parents. The process of sexual reproduction alternates between forms that contain single copies of the genome (haploid) and double copies (diploid).[37] Haploid cells fuse and combine genetic material to create a diploid cell with paired chromosomes. Diploid organisms form haploids by dividing, without replicating their DNA, to create daughter cells that randomly inherit one of each pair of chromosomes. Most animals and many plants are diploid for most of their lifespan, with the haploid form reduced to single cell gametes such as sperm or eggs.

Although they do not use the haploid/diploid method of sexual reproduction, bacteria have many methods of acquiring new genetic information. Some bacteria can undergo conjugation, transferring a small circular piece of DNA to another bacterium.[51] Bacteria can also take up raw DNA fragments found in the environment and integrate them into their genomes, a phenomenon known as transformation.[52] These processes result in horizontal gene transfer, transmitting fragments of genetic information between organisms that would be otherwise unrelated.

The diploid nature of chromosomes allows for genes on different chromosomes to assort independently or be separated from their homologous pair during sexual reproduction wherein haploid gametes are formed. In this way new combinations of genes can occur in the offspring of a mating pair. Genes on the same chromosome would theoretically never recombine. However, they do via the cellular process of chromosomal crossover. During crossover, chromosomes exchange stretches of DNA, effectively shuffling the gene alleles between the chromosomes.[53] This process of chromosomal crossover generally occurs during meiosis, a series of cell divisions that creates haploid cells.

The first cytological demonstration of crossing over was performed by Harriet Creighton and Barbara McClintock in 1931. Their research and experiments on corn provided cytological evidence for the genetic theory that linked genes on paired chromosomes do in fact exchange places from one homolog to the other.

The probability of chromosomal crossover occurring between two given points on the chromosome is related to the distance between the points. For an arbitrarily long distance, the probability of crossover is high enough that the inheritance of the genes is effectively uncorrelated.[54] For genes that are closer together, however, the lower probability of crossover means that the genes demonstrate genetic linkage; alleles for the two genes tend to be inherited together. The amounts of linkage between a series of genes can be combined to form a linear linkage map that roughly describes the arrangement of the genes along the chromosome.[55]

Genes generally express their functional effect through the production of proteins, which are complex molecules responsible for most functions in the cell. Proteins are made up of one or more polypeptide chains, each of which is composed of a sequence of amino acids, and the DNA sequence of a gene (through an RNA intermediate) is used to produce a specific amino acid sequence. This process begins with the production of an RNA molecule with a sequence matching the gene's DNA sequence, a process called transcription.

This messenger RNA molecule is then used to produce a corresponding amino acid sequence through a process called translation. Each group of three nucleotides in the sequence, called a codon, corresponds either to one of the twenty possible amino acids in a protein or an instruction to end the amino acid sequence; this correspondence is called the genetic code.[56] The flow of information is unidirectional: information is transferred from nucleotide sequences into the amino acid sequence of proteins, but it never transfers from protein back into the sequence of DNAa phenomenon Francis Crick called the central dogma of molecular biology.[57]

The specific sequence of amino acids results in a unique three-dimensional structure for that protein, and the three-dimensional structures of proteins are related to their functions.[58][59] Some are simple structural molecules, like the fibers formed by the protein collagen. Proteins can bind to other proteins and simple molecules, sometimes acting as enzymes by facilitating chemical reactions within the bound molecules (without changing the structure of the protein itself). Protein structure is dynamic; the protein hemoglobin bends into slightly different forms as it facilitates the capture, transport, and release of oxygen molecules within mammalian blood.

A single nucleotide difference within DNA can cause a change in the amino acid sequence of a protein. Because protein structures are the result of their amino acid sequences, some changes can dramatically change the properties of a protein by destabilizing the structure or changing the surface of the protein in a way that changes its interaction with other proteins and molecules. For example, sickle-cell anemia is a human genetic disease that results from a single base difference within the coding region for the -globin section of hemoglobin, causing a single amino acid change that changes hemoglobin's physical properties.[60] Sickle-cell versions of hemoglobin stick to themselves, stacking to form fibers that distort the shape of red blood cells carrying the protein. These sickle-shaped cells no longer flow smoothly through blood vessels, having a tendency to clog or degrade, causing the medical problems associated with this disease.

Some DNA sequences are transcribed into RNA but are not translated into protein productssuch RNA molecules are called non-coding RNA. In some cases, these products fold into structures which are involved in critical cell functions (e.g. ribosomal RNA and transfer RNA). RNA can also have regulatory effects through hybridization interactions with other RNA molecules (e.g. microRNA).

Although genes contain all the information an organism uses to function, the environment plays an important role in determining the ultimate phenotypes an organism displays. This is the complementary relationship often referred to as "nature and nurture". The phenotype of an organism depends on the interaction of genes and the environment. An interesting example is the coat coloration of the Siamese cat. In this case, the body temperature of the cat plays the role of the environment. The cat's genes code for dark hair, thus the hair-producing cells in the cat make cellular proteins resulting in dark hair. But these dark hair-producing proteins are sensitive to temperature (i.e. have a mutation causing temperature-sensitivity) and denature in higher-temperature environments, failing to produce dark-hair pigment in areas where the cat has a higher body temperature. In a low-temperature environment, however, the protein's structure is stable and produces dark-hair pigment normally. The protein remains functional in areas of skin that are colder such as its legs, ears, tail and face so the cat has dark-hair at its extremities.[61]

Environment plays a major role in effects of the human genetic disease phenylketonuria.[62] The mutation that causes phenylketonuria disrupts the ability of the body to break down the amino acid phenylalanine, causing a toxic build-up of an intermediate molecule that, in turn, causes severe symptoms of progressive mental retardation and seizures. However, if someone with the phenylketonuria mutation follows a strict diet that avoids this amino acid, they remain normal and healthy.

A popular method for determining how genes and environment ("nature and nurture") contribute to a phenotype involves studying identical and fraternal twins, or other siblings of multiple births.[63] Because identical siblings come from the same zygote, they are genetically the same. Fraternal twins are as genetically different from one another as normal siblings. By comparing how often a certain disorder occurs in a pair of identical twins to how often it occurs in a pair of fraternal twins, scientists can determine whether that disorder is caused by genetic or postnatal environmental factors whether it has "nature" or "nurture" causes. One famous example is the multiple birth study of the Genain quadruplets, who were identical quadruplets all diagnosed with schizophrenia.[64] However such tests cannot separate genetic factors from environmental factors affecting fetal development.

The genome of a given organism contains thousands of genes, but not all these genes need to be active at any given moment. A gene is expressed when it is being transcribed into mRNA and there exist many cellular methods of controlling the expression of genes such that proteins are produced only when needed by the cell. Transcription factors are regulatory proteins that bind to DNA, either promoting or inhibiting the transcription of a gene.[65] Within the genome of Escherichia coli bacteria, for example, there exists a series of genes necessary for the synthesis of the amino acid tryptophan. However, when tryptophan is already available to the cell, these genes for tryptophan synthesis are no longer needed. The presence of tryptophan directly affects the activity of the genestryptophan molecules bind to the tryptophan repressor (a transcription factor), changing the repressor's structure such that the repressor binds to the genes. The tryptophan repressor blocks the transcription and expression of the genes, thereby creating negative feedback regulation of the tryptophan synthesis process.[66]

Differences in gene expression are especially clear within multicellular organisms, where cells all contain the same genome but have very different structures and behaviors due to the expression of different sets of genes. All the cells in a multicellular organism derive from a single cell, differentiating into variant cell types in response to external and intercellular signals and gradually establishing different patterns of gene expression to create different behaviors. As no single gene is responsible for the development of structures within multicellular organisms, these patterns arise from the complex interactions between many cells.

Within eukaryotes, there exist structural features of chromatin that influence the transcription of genes, often in the form of modifications to DNA and chromatin that are stably inherited by daughter cells.[67] These features are called "epigenetic" because they exist "on top" of the DNA sequence and retain inheritance from one cell generation to the next. Because of epigenetic features, different cell types grown within the same medium can retain very different properties. Although epigenetic features are generally dynamic over the course of development, some, like the phenomenon of paramutation, have multigenerational inheritance and exist as rare exceptions to the general rule of DNA as the basis for inheritance.[68]

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, called mutations, can affect the phenotype of an organism, especially if they occur within the protein coding sequence of a gene. Error rates are usually very low1 error in every 10100million basesdue to the "proofreading" ability of DNA polymerases.[69][70] Processes that increase the rate of changes in DNA are called mutagenic: mutagenic chemicals promote errors in DNA replication, often by interfering with the structure of base-pairing, while UV radiation induces mutations by causing damage to the DNA structure.[71] Chemical damage to DNA occurs naturally as well and cells use DNA repair mechanisms to repair mismatches and breaks. The repair does not, however, always restore the original sequence.

In organisms that use chromosomal crossover to exchange DNA and recombine genes, errors in alignment during meiosis can also cause mutations.[72] Errors in crossover are especially likely when similar sequences cause partner chromosomes to adopt a mistaken alignment; this makes some regions in genomes more prone to mutating in this way. These errors create large structural changes in DNA sequence duplications, inversions, deletions of entire regions or the accidental exchange of whole parts of sequences between different chromosomes (chromosomal translocation).

Mutations alter an organism's genotype and occasionally this causes different phenotypes to appear. Most mutations have little effect on an organism's phenotype, health, or reproductive fitness.[73] Mutations that do have an effect are usually deleterious, but occasionally some can be beneficial.[74] Studies in the fly Drosophila melanogaster suggest that if a mutation changes a protein produced by a gene, about 70 percent of these mutations will be harmful with the remainder being either neutral or weakly beneficial.[75]

Population genetics studies the distribution of genetic differences within populations and how these distributions change over time.[76] Changes in the frequency of an allele in a population are mainly influenced by natural selection, where a given allele provides a selective or reproductive advantage to the organism,[77] as well as other factors such as mutation, genetic drift, genetic draft,[78]artificial selection and migration.[79]

Over many generations, the genomes of organisms can change significantly, resulting in evolution. In the process called adaptation, selection for beneficial mutations can cause a species to evolve into forms better able to survive in their environment.[80] New species are formed through the process of speciation, often caused by geographical separations that prevent populations from exchanging genes with each other.[81] The application of genetic principles to the study of population biology and evolution is known as the "modern synthesis".

By comparing the homology between different species' genomes, it is possible to calculate the evolutionary distance between them and when they may have diverged. Genetic comparisons are generally considered a more accurate method of characterizing the relatedness between species than the comparison of phenotypic characteristics. The evolutionary distances between species can be used to form evolutionary trees; these trees represent the common descent and divergence of species over time, although they do not show the transfer of genetic material between unrelated species (known as horizontal gene transfer and most common in bacteria).[82]

Although geneticists originally studied inheritance in a wide range of organisms, researchers began to specialize in studying the genetics of a particular subset of organisms. The fact that significant research already existed for a given organism would encourage new researchers to choose it for further study, and so eventually a few model organisms became the basis for most genetics research.[83] Common research topics in model organism genetics include the study of gene regulation and the involvement of genes in development and cancer.

Organisms were chosen, in part, for convenienceshort generation times and easy genetic manipulation made some organisms popular genetics research tools. Widely used model organisms include the gut bacterium Escherichia coli, the plant Arabidopsis thaliana, baker's yeast (Saccharomyces cerevisiae), the nematode Caenorhabditis elegans, the common fruit fly (Drosophila melanogaster), and the common house mouse (Mus musculus).

Medical genetics seeks to understand how genetic variation relates to human health and disease.[84] When searching for an unknown gene that may be involved in a disease, researchers commonly use genetic linkage and genetic pedigree charts to find the location on the genome associated with the disease. At the population level, researchers take advantage of Mendelian randomization to look for locations in the genome that are associated with diseases, a method especially useful for multigenic traits not clearly defined by a single gene.[85] Once a candidate gene is found, further research is often done on the corresponding gene the orthologous gene in model organisms. In addition to studying genetic diseases, the increased availability of genotyping methods has led to the field of pharmacogenetics: the study of how genotype can affect drug responses.[86]

Individuals differ in their inherited tendency to develop cancer,[87] and cancer is a genetic disease.[88] The process of cancer development in the body is a combination of events. Mutations occasionally occur within cells in the body as they divide. Although these mutations will not be inherited by any offspring, they can affect the behavior of cells, sometimes causing them to grow and divide more frequently. There are biological mechanisms that attempt to stop this process; signals are given to inappropriately dividing cells that should trigger cell death, but sometimes additional mutations occur that cause cells to ignore these messages. An internal process of natural selection occurs within the body and eventually mutations accumulate within cells to promote their own growth, creating a cancerous tumor that grows and invades various tissues of the body.

Normally, a cell divides only in response to signals called growth factors and stops growing once in contact with surrounding cells and in response to growth-inhibitory signals. It usually then divides a limited number of times and dies, staying within the epithelium where it is unable to migrate to other organs. To become a cancer cell, a cell has to accumulate mutations in a number of genes (37) that allow it to bypass this regulation: it no longer needs growth factors to divide, it continues growing when making contact to neighbor cells, and ignores inhibitory signals, it will keep growing indefinitely and is immortal, it will escape from the epithelium and ultimately may be able to escape from the primary tumor, cross the endothelium of a blood vessel, be transported by the bloodstream and will colonize a new organ, forming deadly metastasis. Although there are some genetic predispositions in a small fraction of cancers, the major fraction is due to a set of new genetic mutations that originally appear and accumulate in one or a small number of cells that will divide to form the tumor and are not transmitted to the progeny (somatic mutations). The most frequent mutations are a loss of function of p53 protein, a tumor suppressor, or in the p53 pathway, and gain of function mutations in the ras proteins, or in other oncogenes.

DNA can be manipulated in the laboratory. Restriction enzymes are commonly used enzymes that cut DNA at specific sequences, producing predictable fragments of DNA.[89] DNA fragments can be visualized through use of gel electrophoresis, which separates fragments according to their length.

The use of ligation enzymes allows DNA fragments to be connected. By binding ("ligating") fragments of DNA together from different sources, researchers can create recombinant DNA, the DNA often associated with genetically modified organisms. Recombinant DNA is commonly used in the context of plasmids: short circular DNA molecules with a few genes on them. In the process known as molecular cloning, researchers can amplify the DNA fragments by inserting plasmids into bacteria and then culturing them on plates of agar (to isolate clones of bacteria cells). ("Cloning" can also refer to the various means of creating cloned ("clonal") organisms.)

DNA can also be amplified using a procedure called the polymerase chain reaction (PCR).[90] By using specific short sequences of DNA, PCR can isolate and exponentially amplify a targeted region of DNA. Because it can amplify from extremely small amounts of DNA, PCR is also often used to detect the presence of specific DNA sequences.

DNA sequencing, one of the most fundamental technologies developed to study genetics, allows researchers to determine the sequence of nucleotides in DNA fragments. The technique of chain-termination sequencing, developed in 1977 by a team led by Frederick Sanger, is still routinely used to sequence DNA fragments.[91] Using this technology, researchers have been able to study the molecular sequences associated with many human diseases.

As sequencing has become less expensive, researchers have sequenced the genomes of many organisms, using a process called genome assembly, which utilizes computational tools to stitch together sequences from many different fragments.[92] These technologies were used to sequence the human genome in the Human Genome Project completed in 2003.[34] New high-throughput sequencing technologies are dramatically lowering the cost of DNA sequencing, with many researchers hoping to bring the cost of resequencing a human genome down to a thousand dollars.[93]

Next generation sequencing (or high-throughput sequencing) came about due to the ever-increasing demand for low-cost sequencing. These sequencing technologies allow the production of potentially millions of sequences concurrently.[94][95] The large amount of sequence data available has created the field of genomics, research that uses computational tools to search for and analyze patterns in the full genomes of organisms. Genomics can also be considered a subfield of bioinformatics, which uses computational approaches to analyze large sets of biological data. A common problem to these fields of research is how to manage and share data that deals with human subject and personally identifiable information. See also genomics data sharing.

On 19 March 2015, a leading group of biologists urged a worldwide ban on clinical use of methods, particularly the use of CRISPR and zinc finger, to edit the human genome in a way that can be inherited.[96][97][98][99] In April 2015, Chinese researchers reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[100][101]

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Genetics - Wikipedia

I. Genetics And BehaviorP. L. Broadhurst

BIBLIOGRAPHY

II. Demography and Population GeneticsJean Sutter

BIBLIOGRAPHY

III. Race and GeneticsJ. N. Spuhler

BIBLIOGRAPHY

Behavior genetics is a relatively new cross-disciplinary specialization between genetics and Psychology. It is so new that it hardly knows what to call itself. The term behavior genetics is gaining currency in the United States; but in some quarters there, and certainly elsewhere, the term psycho-genetics is favored. Logically, the best name would be genetical psychology, since the emphasis is on the use of the techniques of genetics in the analysis of behavior rather than vice versa; but the in evitable ambiguity of that term is apparent. Psy chologists generally use the terms genetic or genetical in two senses: in the first and older sense of developmental, or ontogenetic; and in the second, more recent usage relating to the analysis of inheritance. The psychologist G. Stanley Hall coined the term genetic before the turn of the century to denote developmental studies (witness the Journal of Genetic Psychology), and Alfred Binet even used the term psychogenetic in this sense. But with the rapid rise of the discipline now known as genetics after the rediscovery of the Mendelian laws in 1900, William Bateson, one of the founders of this new science, pre-empted the term genetic in naming it, thereby investing genetic with the double meaning that causes the current confusion. Psychological genetics, with its obvious abbreviation, psychogenetics, is probably the best escape from the dilemma.

Importance of genetics in behavior. The importance of psychogenetics lies in the fundamental nature of the biological processes in our understanding of human social behavior. The social sciences, and psychology in particular, have long concentrated on environmental determinants of behavior and neglected hereditary ones. But it is clear that in many psychological functions a substantial portion of the observed variation, roughly of the order of 50 per cent for many traits, can be ascribed to hereditary causation. To ignore this hereditary contribution is to impede both action and thought in this area.

This manifold contribution to behavioral variation is not a static affair. Heredity and environment interact, and behavior is the product, rather than the sum, of their respective contributions. The number of sources of variability in both he redity and environment is large, and the consequent number of such possible products even larger. Nevertheless, these outcomes are not incalculable, and experimental and other analyses of their limits are of immense potential interest to the behavioral scientist. The chief theoretical interest lies in the analysis of the evolution of behavior; and the chief practical significance, so far as can be envisaged at present, lies in the possibilities psychogenetics has for the optimization of genetic potential by manipulation of the environmental expression of it.

Major current approaches. The major approaches to the study of psychogenetics can be characterized as the direct, or experimental, and the indirect, or observational. The former derive principally from the genetical parent of this hybrid discipline and involve the manipulation of the heredity of experimental subjects, usually by restricting the choice of mates in some specially defined way. Since such techniques are not possible with human subjects a second major approach exists, the indirect or observational, with its techniques derived largely from psychology and sociology. The two approaches are largely complementary in the case of natural genetic experiments in human populations, such as twinning or cousin marriages. Thus, the distinction between the two is based on the practicability of controlling in some way the essentially immutable genetic endowmentin a word, the genotypeof the individuals subject to investigation. With typical experimental animals (rats, mice, etc.) and other organisms used by the geneticist, such as the fruit fly and many microorganisms, the genotype can often be specified in advance and populations constructed by the hybridization of suitable strains to meet this specification with a high degree of accuracy. Not so with humans, where the genotype must remain as given, and indeed where its details can rarely be specified with any degree of accuracy except for certain physical characteristics, such as blood groups. Observational, demographic, and similar techniques are therefore all that are available here. The human field has another disadvantage in rigorous psychogenetic work: the impossibility of radically manipulating the environmentfor example, by rearing humans in experimental environ ments from birth in the way that can easily be done with animals in the laboratory. Since in psychogenetics, as in all branches of genetics, one deals with a phenotypein this case, behavior and since the phenotype is the end product of the action, or better still, interaction of genotype and environment, human psychogenetics is fraught with double difficulty. Analytical techniques to be mentioned later can assist in resolving some of these difficulties.

Definition. To define psychogenetics as the study of the inheritance of behavior is to adopt a misleadingly narrow definition of the area of study, and one which is unduly restrictive in its emphasis on the hereditarian point of view. Just as the parent discipline of genetics is the analysis not only of the similarities between individuals but also of the differences between them, so psychogenetics seeks to understand the basis of individual differences in behavior. Any psychogenetic analysis must therefore be concerned with the environmental determinants of behavior (conventionally implicated in the genesis of differences) in addition to the hereditary ones (the classic source of resemblances). But manifestly this dichotomy does not always operate, so that for this reason alone the analysis of environmental effects must go hand in hand with the search for genetic causation. This is true even if the intention is merely to exclude the influence of the one the better to study the other; but the approach advocated here is to study the two in tandem, as it were, and to determine the extent to which the one interacts with the other. Psychogenetics is best viewed as that specialization which concerns itself with the interaction of heredity and environment, insofar as they affect behavior. To attempt greater precision is to become involved in subtle semantic problems about the meanings of terms.

At first sight many would tend to restrict environmental effects to those operating after the birth of the organism, but to do so would be to exclude prenatal environmental effects that have been shown to be influential in later behavior. On the other hand, to broaden the concept of environment to include all influences after fertilization the point in time at which the genotype is fixed permits consideration of the reciprocal influence of parts of the genotype upon each other. Can environment include the rest of the genotype, other than that part which is more or less directly concerned with the phenotype under consideration? This point assumes some importance since there are characteristics, not behavioralat least, none that are behavioral have so far been reported whose expression depends on the nature of the other genes present in the organism. In the absence of some of them, or rather certain alleles of the gene pairs, the value phenotypically observed would be different from what it would be if they were present. That is, different components of the genotype, in interplay with one another, modify phenotypic expression of the characteristic they in fluence. Can such indirect action, which recalls that of a chemical catalyst, best be considered as environmental or innate? It would be preferable to many to regard this mechanism as a genetic effect rather than an environmental one in the usually accepted sense. Hence, the definition of the area of study as one involving the interaction of heredity and environment, while apparently adding complexity, in fact serves to reduce confusion.

It must be conceded that this view has not as yet gained general acceptance. In some of the work reviewed in the necessarily brief survey of the major findings in this area, attempts have been made to retain a rather rigid dichotomy between heredity and environmentnature versus nurture in fact, an either/or proposition that the facts do not warrant. The excesses of both sides in the controversies of the 1920sfor example, the famous debate between Watson and McDougall over the relative importance of learned (environmental) and instinctive (genetic) determinants of behavior show the fallacies that extreme protagonists on either side can entertain if the importance of the interaction effect is ignored.

Gene action. The nature of gene action as such is essentially conducive to interaction with the environment, since the behavioral phenotype we observe is the end product of a long chain of action, principally biochemical, originating in the chromosome within the individual cell. A chromosome has a complex structure, involving DNA (deoxyribonucleic acid) and the connections of DNA with various proteins, and may be influenced in turn by another nucleic acid, RNA (ribonucleic acid), also within the cell but external to the nucleus. There are complex structures and sequences of processes, anatomical, physiological, and hormonal, which underlie normal development and differentiation of structure and function in the growth, development, and maturation of the organism. Much of this influence is determined genetically in the sense that the genotype of the organism, fixed at conception, determines how it proceeds under normal environmental circumstances. But it would be a mistake to regard any such sequence as rigid or immutable, as we shall see.

The state of affairs that arises when a number of genetically determined biochemical abnormalities affect behavior is illustrative of the argument. Many of these biochemical deficiencies or inborn errors of metabolism in humans are the outcome of a chain of causation starting with genie structures, some of them having known chromosomal locations. Their effects on the total personalitythat is, the sum total of behavorial variation that makes the individual uniquecan range from the trivial to the intense. The facility with which people can taste a solution of phenylthiocarbamide (PTC), a synthetic substance not found in nature, varies in a relatively simple genetical way: people are either tasters or nontasters in certain rather well-defined proportions, with a pattern of inheritance determined probably by one gene of major effect. But being taste blind or not is a relatively unimportant piece of behavior, since one is never likely to encounter it outside a genetical experiment. (It should perhaps be added that there is some evidence that the ability to taste PTC may be linked with other characteristics of some importance, such as susceptibility to thyroid disease.) Nevertheless, this example is insignificant compared with the psychological effect of the absence of a biochemical link in patients suffering from phenylketonuria. They are unable to metabolize phenylalanine to tyrosine in the liver, with the result that the phenylalanine accumulates and the patient suffers multiple defects, among which is usually gross intellectual defect, with an IQ typically on the order of 30. This gross biochemical failure is mediated by a single recessive gene that may be passed on in a family unnoticed in heterozygoussingle doseform but becomes painfully apparent in the unfortunate individual who happens to receive a double dose and consequently is homozygous for the defect.

Alternatively, a normal dominant gene may mutate to the recessive form and so give rise to the trouble. While mutation is a relatively rare event individually, the number of genes in each individualprobably on the order of ten thousand and the number of individuals in a population make it statistically a factor to be reckoned with. One of the best documented cases of a deleterious mutation of this kind giving rise to a major defect relates to the hemophilia transmitted, with certain important political consequences, to some of the descendants of Queen Victoria of England. The dependence of the last tsarina of Russia on the monk Rasputin was said to be based in part on the beneficial therapeutic effect of his hypnotic techniques on the uncontrollable bleeding of the Tsarevitch Alexis. Victoria was almost certainly heterozygous for hemophilia and, in view of the absence of any previous record of the defect in the Hanoverian dynasty, it seems likely that the origin of the trouble was a mutation in one of the germ cells in a testicle of Victorias father, the duke of Kent, before Victoria was conceived in August 1818.

But however it comes about, a defect such as phenylketonuria can be crippling. Fortunately, its presence can be diagnosed in very early life by a simple urine test for phenyl derivatives. The dependence of the expression of the genetic defect on the environmental circumstances is such that its effect can be mitigated by feeding the afflicted infant with a specially composed diet low in the phenylalanine with which the patients biochemical make-up cannot cope. Here again, therefore, one sees the interaction of genotype and environment in this case the type of food eaten. Many of the human biochemical defects that have been brought to light in recent years are rather simply determined genetically, in contrast with the prevailing beliefs about the bases of many behavioral characteristics including intelligence, personality, and most psychotic and neurotic disorders. This is also true of several chromosomal aberrations that have been much studied recently and that are now known to be implicated in various conditions of profound behavioral importance. Prominent among these is Downs syndrome (mongolism) with, again, effects including impairment of cognitive power. [SeeIntelligence and Intelligence Testing; Mental Disorders, articles onBiological AspectsandGenetic Aspects.]

Sex as a genetic characteristic. The sex difference is perhaps the most striking genetically determined difference in behavior and the one that is most often ignored in this connection. Primary sex is completely determined genetically at the moment of fertilization of the ovum; in mammals sex depends on whether the spermatozoon effecting fertilization bears an X or a Y chromosome to combine with the X chromosome inevitably contributed by the ovum. The resulting gamete then has the form of an XX (female) or an XY (male) individual. This difference penetrates every cell of every tissue of the resulting individual and in turn is responsible for the observable gross differences in morphology. These, in turn, subserve differences of physiological function, metabolism, and endocrine function which profoundly influence not only those aspects of behavior relating to sexual behav ior and reproductive function in the two sexes but many other aspects as well. But behavior is also influenced by social and cultural pressures, so that the resulting sex differences in behavior as observed by the psychologist are especially good examples of a phenotype that must be the and product of both genetic and environmental forces. There is a large literature on sex differences in human behavior and a sizable one on such differ ences in animal behavior, but there has been little attempt to assess this pervasive variation in terms of the relative contribution of genetic and environmental determinants. This is partly because of the technical difficulties of the problem, in the sense that all subjects must be of either one sex or the othercrossing males with females will always result in the same groups as those one started with, either males or femalesthere being, in general, no genetically intermediate sex against which to evaluate either and identical twins being inevitably of like sex. It is also partly because the potential of genetic analyses that do not involve direct experi mentation has not been realized. This is especially so since the causal routes whereby genetic determinants of sex influence many of the behavioral phenotypes observed are often better understood than in other cases where the genetic determinants underlying individual differences manifest in a population are not so clear-cut. [SeeIndividualDifferences, article onSex Differences.]

Sex linkage. There is one exception to the general lack of interest in the biometrical analysis of sex differences having behavioral connotations: sex-linked conditions. That is to say, it is demonstrated or postulated that the gene or genes responsible for the behavioroften a defect, as in the case of color blindness, which has a significantly greater incidence in males than in femalesare linked with the sex difference by virtue of their location on the sex chromosome determining genetic sex. Thus it is that sex can be thought of as a chromosomal difference of regular occurrence, as opposed to aberrations of the sort which give rise to pathological conditions, such as Downs syndrome. Indeed there are also various anomalies of genetic sex that give rise to problems of sexual identity, in which the psychological and overt be havioral consequences can be of major importance for the individual. While the evidence in such cases of environmental modification of the causative genetic conditions is less dramatic than in phenylketonuria, interaction undoubtedly exists, since these chromosomal defects of sex differentiation can in some cases be alleviated by appropriate surgical and hormonal treatment. [SeeSexual BEHavior, article onSexual Deviation: Psychological Aspects; andVision, article onColor Vision and Color Blindness.]

Human psychogenetics. It is abundantly clear that most of the phenotypes the behavioral scientist is interested in are multidetermined, both environmentally and genetically. The previous examples, however, are the exception rather than the rule, and their prominence bears witness that our understanding of genetics and behavior is as yet so little advanced that the simpler modes of genetic expression have been the first to be explored. In genetics itself, the striking differences in seed configuration used by Mendel in his classic crosses of sweet peas are determined by major genes with full dominance acting simply. But such clear-cut expression, especially of dominance, is unusual in human psychogenetics, and more complex statistical techniques are necessary to evaluate multiple genetic and environmental effects acting to produce the observed phenotype.

Whatever the analysis applied to the data gathered in other fields, in human psychogenetics the method employed cannot be the straightforward Mendelian one of crossbreeding which, in various elaborations, remains the basic tool of the geneticist today. Neither can it be the method of selection artificial, as opposed to naturalthat is other wise known as selective breeding. Indeed, none of the experimental techniques that can be applied to any other organism, whatever the phenotype being measured, is applicable to man, since experimental mating is effectively ruled out as a permissible technique in current cultures. It may be remarked in passing that such has not always been the case. The experiment of the Mogul emperor, Akbar, who reared children in isolation to determine their natural religion (and merely produced mutes) and the eugenics program of J. H. Noyes at the Oneida Community in New York State in the nineteenth century are cases in point. The apparent inbreeding of brother with sister among the rulers of ancient Egypt in the eighteenth dynasty (sixteenth to fourteenth century B.C.), which is often quoted as an example of the absence in humans of the deleterious effects of inbreeding (inbreeding depression), may not be all it seems. It is likely that the definition of sister and brother in this context did not necessarily have the same biological relevance that it has today but was rather a cultural role that could be defined, at least in this case, at will.

Twin study. In the absence of the possibility of an experimental approach, contemporary re search in human psychogenetics must rely on natural genetic experiments. Of these, the one most widely used and most industriously studied is the phenomenon of human twinning. Credit for the recognition of the value of observations on twins can be given to the nineteenth-century English scientist entist Francis Galton, who pioneered many fields of inquiry. He may be justly regarded as the father of psychogenetics for the practical methods he introduced into this field, such as the method of twin study, as well as for his influence which extended, although indirectly, even to the American experimenters in psychogenetics during the early decades of the present century.

Twin births are relatively rare in humans and vary in frequency with the ethnic group. However, the extent to which such ethnic groups differ among themselves behaviorally as a result of the undoubted genetic differences, of which incidence of multiple births is but one example, is controversial. As is well known, there are two types of twins: the monozygotic or so-called identical twins, derived from a single fertilized ovum that has split into two at an early stage in development, and the dizygotic or so-called fraternal twins, developed from two separate ova fertilized by different spermatozoa. These two physical types are not always easy to differentiate, although this difficulty is relatively miner in twin study. Nonetheless, they have led to two kinds of investigation. The first relates to differences in monozygotic twins who have identical hereditary make-up but who have been reared apart and thus subjected to different environmental influences during childhood; and the second relates to the comparison of the two types of twins usually restricted to like-sex pairs, since fraternal twins can differ in sex. The latter method supposes all differences between monozygotic pairs to be due to environmental origin, whereas the (greater) difference between dizygotic pairs is of environmental plus genetic origin. Thus, the relative contribution of the two sources of variation can be evaluated.

Findings obtained from either method have not been especially clear-cut, both because of intractable problems regarding the relative weight to be placed upon differences in the environment in which the twins have been reared and because of the sampling difficulties, which are likely to be formidable in any twin study. Nevertheless, interesting inferences can be drawn from twin study. The investigation of separated monozygotic twins has shown that while even with their identical heredity they can differ quite widely, there exists a significant resemblance in basic aspects of personality including intelligence, introversion, and neurotic tendencies, and that these resemblances can persist despite widely different environments in which the members of a pair are reared. Such findings emphasize the need to consider the contribution of genotype and environment in an inter active senseclearly some genotypes represented in the personality of monozygotic twin pairs are sensitive to environmentally induced variation, whereas others are resistant to it.

Comparisons between monozygotic and dizygotic twins reared together suggest that monozygotic twins more closely resemble each other in many aspects of personality, especially those defining psychological factors such as neuroticism and introversion-extroversion. The increase in the differences between the two types of twins when factor measures are usedas opposed to simple test scoressuggests that a more basic biological stratum is tapped by factor techniques, since the genetic determination seems greater than where individual tests are employed. Here again, the de gree to which any phenotype is shown to be hereditary in origin is valid only for the environment in which it developed and is measured; different environments may well yield different results. The problems of environmental control in human samples are so intractable that some students of the subject have questioned whether the effort and undoubted skill devoted to twin study have been well invested, in view of the inherent and persisting equivocality of the outcome.

Multivariate methods. Methods of twin study, introduced largely to improve upon the earlier methods of familial correlation (parents with off spring, sib with sib, etc.), have been combined with them. Familial correlation methods them selves have not been dealt with here, since within-family environments are bound to be even greater contaminants in determining the observed behavior than environments in twin study methods. Never theless, used on a large scale and in conjunction with twin study and with control subjects selected at random from a population, multivariate methods show promise for defining the limits of environmental and genotypic interaction. So far, the solutions to the problems of biometrical analysis posed by this type of investigation have been only partial, and the sheer weight of effort involved in locating and testing the requisite numbers of subjects standing in the required relationships has deterred all but a few pioneers. Despite the undoubtedly useful part such investigations have played in defining the problems involved, the absence of the possibility of experimental breeding has proved a drawback in the provision of socially useful data.

Animal psychogenetics. Recourse has often been had to nonhuman subjects. The additional problem thereby incurred of the relevance of comparative data to human behavior is probably balanced by the double refinements of the control of both the heredity and the environment of the experimental subjects. Two major methods of genetics have been employed, both intended to produce subjects of predetermined genotype: the crossbreeding of strains of animals of known genotype; and phenotypic selection, the mating of like with like to increase a given characteristic in a population.

Selection. Behavioral phenotypes of interest have been studied by the above methods, often using laboratory rodents. For example, attributes such as intelligence, activity, speed of conditioning, and emotionality have been selectively bred in rats.

Selection for emotional behavior in the rat will serve as an example of the techniques used and the results achieved. Rats, in common with many other mammalian species, defecate when afraid. A technique of measuring individual differences in emotional arousal is based on this propensity. The animal under test is exposed to mildly stressful noise and light stimulation in an open field or arena. The number of fecal pellets deposited serves as an index of disturbance, and in this way the extremes among a large group of rats can be characterized as high or low in emotional responsiveness. Continued selection from within the high and low groups will in time produce two distinct strains. Control of environmental variables is achieved by a rigid standardization of the conditions under which the animals are reared before being subjected to the test as adults. Careful checks on maternal effects, both prenatal and postnatal, reveal these effects to be minimal.

Such an experiment does little beyond establishing the importance of the genetic effect on the given strains in the given environment. While there are techniques for assessing the relative importance of the genetic and environmental contributions to the variation observed under selection, they are better suited to the analysis of the outcome of experiments using the alternative major genetical method, that of crossbreeding of inbred strains.

Crossbreeding. Strains used in crossbreeding experiments have usually been inbred for a phenotypic character of interest, although not usually a behavioral one. However, this does not preclude the use of these inbred strains for behavioral studies, since linkage relationships among genes ensure that selection for factors multidetermined genetically often involves multiple changes in characteristics other than those selected for, and behavior is no exception to this rule. Moreover, the existence of such inbred strains constitutes perhaps the most important single advantage of animals as subjects, since it enables simplifying assumptions regarding the homozygosity or genetic uniformity of such strains to be made in analysis of the outcome of crosses. Members of inbred strains are theoretically as alike as monozygotic twin pairs, so that genetic relationshipswhich in human populations can be investigated only after widespread efforts to find themcan be multiplied at will in laboratory animals.

This approach allows a more sensitive analysis of the determinants, both environmental and genetic, of the behavioral phenotype under observation. In addition, the nature of the genetic forces can be further differentiated into considerations of the average dominance effects of the genes in volved, the extent to which they tend to increase or decrease the metrical expression of the behavioral phenotype, and the extent to which the different strains involved possess such increasers or de creases. Finally, rough estimates of the number of these genes can be given. But the analysis depends upon meeting requirements regarding the scaling of the metric upon which the behavior is measured and is essentially a statistical one. That is, only average effects of cumulative action of the relatively large number of genes postulated as in volved can be detected. Gone are the elegantly simple statistics derived from the classical Men-delian analyses of genes of major effect, often displaying dominance, like those encountered incertain human inborn errors of metabolism. There is little evidence of the existence of comparable genes of major effect mediating behavior in laboratory animals, although some have been studied in in sects, especially the fruit fly.

A typical investigation of a behavioral phenotype might take the form of identifying two inbred strains known to differ in a behavioral trait, measuring individuals from these strains, and then systematically crossing them and measuring all offspring. When this was done for the runway performance of mice, an attribute related to their temperamental wildness, the results, analyzed by the techniques of biometrical genetics, showed that the behavior was controlled by at least three groups of genes (a probable underestimate). The contributions of these groups were additive to each other and independent of the environment when measured on a logarithmic scale but interacted with each other and with the environment on a linear scale. These genes showed a significant average dominance effect, and there was a preponderance of dominant genes in the direction of greater wildness. The heritability ratio of the contributions of nature and nurture was around seven to three.

The use of inbred lines may be restricted to first filial crosses if a number of such crosses are made from several different lines. This increases precision of analysis in addition to allowing a proportionate decrease in the amount of laboratory work. One investigation examined the exploratory behavior of six different strains of rats in an open field of the kind used for the selection mentioned above. On a linear scale there were no untoward environmental effects, including specifically prenatal maternal ones. The heritability ratio was high, around nine to one; and while there was a significant average dominance component among the genes determining exploration, there was no preponderance of dominants or recessively acting genes among increasers or decreasers. The relative standing in this respect of the parental strains could be established with some precision.

Limitations. While the methods described above have allowed the emergence of results that ultimately may assist our understanding of the mechanisms of behavioral inheritance, it cannot be said that much substantial progress has yet been made. Until experiments explore the effect of a range of different genotypes interacting with a range of environments of psychological interest and consequence, little more can be expected. Manipulating heredity in a single standard environment or manipulating the environment of a single standard genotype can only provide conclusions so limited to both the genotypes and conditions employed that they have little usefulness in a wider context. When better experiments are performed, as seems likely in the next few decades, then problems of some sociological importance and interest will arise in the application of these experiments to the tasks of maximizing genetic potential and perfecting environmental control for the purpose of so doing. A new eugenics may well develop, but grappling with the problems of its impact on contemporary society had best be left to future generations.

P. L. Broadhurst

[Directly related are the entriesEugenics; Evolution; Mental Disorders, article onGenetic Aspects. Other relevant material may be found inIndividual Differences, article onSex Differences; Instinct; Intelligence and Intelligence Testing; Mental Ertardation; Psychology, article onConstitutional Psychology.]

Broadhurst, P. L. 1960 Experiments in Psychogenetics: Applications of Biometrical Genetics to the Inheritance of Behavior. Pages 1-102 in Hans J. Eysenck (editor), Experiments in Personality. Volume 1: Psychogenetics and Psychopharmacology. London: Routledge. Selection and crossbreeding methods applied to laboratory rats.

Catteix, RaymondB.; Stice, GlenF.; and Kristy, Nor TonF. 1957 A First Approximation to Nature-Nurture Ratios for Eleven Primary Personality Factors in Objective Tests. Journal of Abnormal and Social Psychology 54:143159. Pioneer multivariate analysis combining twin study and familial correlations.

Fuller, JohnL.; and Thompson, W. Robert 1960 Be havior Genetics. New York: Wiley. A comprehen sive review of the field.

Mather, Kenneth1949 Biometrical Genetics: The Study of Continuous Variation. New York: Dover. The classic work on the analysis of quantitative char acteristics.

Shields, James1962 Monozygotic Twins Brought Up Apart and Brought Up Together: An Investigation Into the Genetic and Environmental Causes of Variation in Personality. Oxford Univ. Press.

The best available definition of population genetics is doubtless that of Malcot: It is the totality of mathematical models that can be constructed to represent the evolution of the structure of a population classified according to the distribution of its Mendelian genes (1955, p. 240). This definition, by a probabilist mathematician, gives a correct idea of the constructed and abstract side of this branch of genetics; it also makes intelligible the rapid development of population genetics since the advent of Mendelism.

In its formal aspect this branch of genetics might even seem to be a science that is almost played out. Indeed, it is not unthinkable that mathematicians have exhausted all the structural possibilities for building models, both within the context of general genetics and within that of the hypothesesmore or less complex and abstractthat enable us to characterize the state of a population.

Two major categories of models can be distinguished: determinist models are those in which variations in population composition over time are rigorously determined by (a) a known initial state of the population; (b) a known number of forces or pressures operating, in the course of generations, in an unambiguously defined fashion (Male-cot 1955, p. 240). These pressures involve mutation, selection, and preferential marriages (by consanguinity, for instance). Determinist models, based on ratios that have been exactly ascertained from preceding phenomena, can be expressed only in terms of populations that are infinite in the mathematical sense. In fact, it is only in this type of population that statistical regularities can emerge (Malecot 1955). In these models the composition of each generation is perfectly defined by the composition of the preceding generation.

Stochastic models, in contrast to determinist ones, involve only finite populations, in which the gametes that, beginning with the first generation, are actually going to give birth to the new generation represent only a finite number among all possible gametes. The result is that among these active, or useful, gametes (Malecot 1959), male or female, the actual frequency of a gene will differ from the probability that each gamete had of carrying it at the outset.

The effect of chance will play a prime role, and the frequencies of the genes will be able to drift from one generation to the other. The effects of random drift and of genetic drift become, under these conditions, the focal points for research.

The body of research completed on these assumptions does indeed form a coherent whole, but these results, in spite of their brilliance, are marked by a very noticeable formalism. In reality, the models, although of great importance at the conceptual level, are often too far removed from the facts. In the study of man, particularly, the problems posed are often too complex for the solutions taken directly from the models to describe concrete reality.

Not all these models, however, are the result of purely abstract speculation; construction of some of them has been facilitated by experimental data. To illustrate this definition of population genetics and the problems that it raises, this article will limit itself to explaining one determinist model, both because it is one of the oldest and simplest to under stand and because it is one of those most often verified by observation.

A determinist model. Let us take the case of a particular human population: the inhabitants of an island cut off from outside contacts. It is obvious that great variability exists among the genes carried by the different inhabitants of this island. The genotypes differ materially from one another; in other words, there is a certain polymorphism in the populationpolymorphism that we can define in genetic terms with the help of a simple example.

Let us take the case of autosome (not connected with sex) gene a, transmitting itself in a mono-hybrid diallely. In relation to it individuals can be classified in three categories: homozygotes whose two alleles are a (a/a); heterozygotes, carriers of a and its allele a (a/a); and the homozygotes who are noncarriers of a (a/a). At any given moment or during any given generation, these three categories of individuals exist within the population in certain proportions relative to each other.

Now, according to Mendels second law (the law of segregation), the population born out of a cross between an individual who is homozygote for a (a/a) and an individual who is homozygote for a (a/a) will include individuals a/a, a/a, and a/a in the following proportions: one-fourth a/a, one-half a/a, and one-fourth a/a. In this popu lation the alleles a and a have the same frequency, one-half, and each sex produces half a and half a. If these individuals are mated randomly, a simple algebraic calculation quickly demonstrates that individuals of the generation following will be quan titatively distributed in the same fashion: one-fourth a/a, one-half a/a, and one-fourth a/a. It will be the same for succeeding generations.

It can therefore be stated that the genetic structure of such a population does not vary from one generation to the other. If we designate by p the initial proportion of a/a individuals and by q that of a/a individuals, we get p + q = 1, or the totality of the population. Applying this system of symbols to the preceding facts, it can be easily shown that the proportion of individuals of all three categories in the first generation born from a/a and a/a equals p2, 2pq, q2. In the second and third generation the frequency of individuals will always be similar: p2, 2pq, q2.

Until this point, we have remained at the individual level. If we proceed to that of the gametes carrying a or a and to that of genes a and a, we observe that their frequencies intermingle. In the type of population discussed above, the formula p2, 2pq, q2 still applies perfectly, therefore, to the gametes and genes. This model, which can be regarded as a formalization of the Hardy-Weinberg law, has other properties, but our study of it will stop here. (For a discussion of the study of isolated populations, see Sutter & Tabah 1951.)

Model construction and demographic reality. The Hardy-Weinberg law has been verified by numerous studies, involving both vegetable and animal species. The findings in the field of human blood groups have also been studied for a long time from a viewpoint derived implicitly from this law, especially in connection with their geographic distribution. Under the system of reproduction by sexes, a generation renews itself as a result of the encounter of the sexual cells (gametes) produced by individuals of both sexes belonging to the living generation. In the human species it can be said that this encounter takes place at random. One can imagine the advantage that formal population genetics can take of this circumstance, which can be compared to drawing marked balls by lot from two different urns. Model construction, already favored by these circumstances, is favored even further if the characteristics of the population utilized are artificially defined with the help of a certain number of hypotheses, of which the following is a summary description:

(1) Fertility is identical for all couples; there is no differential fertility.

(2) The population is closed; it cannot, there fore, be the locus of migrations (whether immigration or emigration).

(3) Marriages take place at random; there is no assortative mating.

(4) There are no systematic preferential marriages (for instance, because of consanguinity).

(5) Possible mutations are not taken into consideration.

(6) The size of the population is clearly denned. On the basis of these working hypotheses, the whole of which constitutes panmixia, it was possible, not long after the rediscovery of Mendels laws, to construct the first mathematical models. Thus, population genetics took its first steps forward, one of which was undoubtedly the Hardy-Weinberg law.

Mere inspection of the preceding hypotheses will enable the reader to judge how, taken one by one, they conflict with reality. In fact, no human population can be panmictic in the way the models are.

The following evidence can be cited in favor of this conclusion:

(1) Fertility is never the same with all couples. In fact, differential fertility is the rule in human populations. There is always a far from negligible sterility rate of about 18 per cent among the large populations of Western civilization. On the other hand, the part played by large families in keeping up the numbers of these populations is extremely important; we can therefore generalize by emphasizing that for one or another reason individ uals carrying a certain assortment of genes reproduce themselves more or less than the average number of couples. That is what makes for the fact that in each population there is always a certain degree of selection. Hypothesis (1) above, essential to the construction of models, is therefore very far removed from reality.

(2) Closed populations are extremely rare. Even among the most primitive peoples there is always a minimum of emigration or immigration. The only cases where one could hope to see this condition fulfilled at the present time would be those of island populations that have remained extremely primitive.

(3) With assortative mating we touch on a point that is still obscure; but even if these phe nomena remain poorly understood, it can nevertheless be said that they appear to be crucial in determining the genetic composition of populations. This choice can be positive: the carriers of a given characteristic marry among each other more often than chance would warrant. The fact was demonstrated in England by Pearson and Lee (1903): very tall individuals have a tendency to marry each other, and so do very short ones. Willoughby (1933) has reported on this question with respect to a great number of somatic characteristics other than heightfor example, coloring of hair, eyes and skin, intelligence quotient, and so forth. Inversely, negative choice makes individuals with the same characteristics avoid marrying one another. This mechanism is much less well known than the above. The example of persons of violent nature (Dahlberg 1943) and of red-headed individuals has been cited many times, although it has not been possible to establish valid statistics to support it.

(4) The case of preferential marriages is not at all negligible. There are still numerous areas where marriages between relatives (consanguineous marriages) occur much more frequently than they would as the result of simple random encounters. In addition, recent studies on the structures of kinship have shown that numerous populations that do not do so today used to practice preferential marriagemost often in a matrilinear sense. These social phenomena have a wide repercussion on the genetic structure of populations and are capable of modifying them considerably from one generation to the other.

(5) Although we do not know exactly what the real rates of mutation are, it can be admitted that their frequency is not negligible. If one or several genes mutate at a given moment in one or several individuals, the nature of the gene or genes is in this way modified; its stability in the population undergoes a disturbance that can considerably transform the composition of that population.

(6) The size of the population and its limits have to be taken into account. We have seen that this is one of the essential characteristics important in differentiating two large categories of models.

The above examination brings us into contact with the realities of population: fertility, fecundity, nuptiality, mortality, migration, and size are the elements that are the concern of demography and are studied not only by this science but also very often as part of administrative routine. Leaving aside the influence of size, which by definition is of prime importance in the technique of the models, there remain five factors to be examined from the demographic point of view. Mutation can be ruled out of consideration, because, although its importance is great, it is felt only after the passage of a certain number of generations. It can therefore be admitted that it is not of immediate interest.

We can also set aside choice of a mate, because the importance of this factor in practice is still unknown. Accordingly, there remain three factors of prime importance: fertility, migration, and preferential marriage. Over the last decade the progressive disappearance of consanguineous marriage has been noted everywhere but in Asia. In many civilized countries marriage between cousins has practically disappeared. It can be stated, therefore, that this factor has in recent years become considerably less important.

Migrations remain very important on the genetic level, but, unfortunately, precise demographic data about them are rare, and most of the data are of doubtful validity. For instance, it is hard to judge how their influence on a population of Western culture could be estimated.

The only remaining factor, fertility (which to geneticists seems essential), has fortunately been studied in satisfactory fashion by demographers. To show the importance of differential fertility in human populations, let us recall a well-known cal culation made by Karl Pearson in connection with Denmark. In 1830, 50 per cent of the children in that country were born of 25 per cent of the parents. If that fertility had been maintained at the same rate, 73 per cent of the second-generation Danes and 97 per cent of the third generation would have been descended from the first 25 per cent. Similarly, before World War I, Charles B. Davenport calculated, on the basis of differential fertility, that 1,000 Harvard graduates would have only 50 descendants after two centuries, while 1,000 Rumanian emigrants living in Boston would have become 100,000.

Human reproduction involves both fecundity (capacity for reproduction) and fertility (actual reproductive performance). These can be estimated for males, females, and married couples treated as a reproductive unit. Let us rapidly review the measurements that demography provides for geneticists in this domain.

Crude birth rate. The number of living births in a calendar year per thousand of the average population in the same year is known as the crude birth rate. The rate does not seem a very useful one for geneticists: there are too many different groups of childbearing age; marriage rates are too variable from one population to another; birth control is not uniformly diffused, and so forth.

General fertility rate. The ratio of the number of live births in one year to the average number of women capable of bearing children (usually defined as those women aged 15 to 49) is known as the general fertility rate. Its genetic usefulness is no greater than that of the preceding figure. Moreover, experience shows that this figure is not very different from the crude birth rate.

Age-specific fertility rates. Fertility rates according to the age reached by the mother during the year under consideration are known as age-specific fertility rates. Demographic experience shows that great differences are observed here, depending on whether or not the populations are Malthusianin other words, whether they practice birth control or not. In the case of a population where the fertility is natural, knowledge of the mothers age is sufficient. In cases where the population is Malthusian, the figure becomes interesting when it is calculated both by age and by age group of the mothers at time of marriage, thus combining the mothers age at the birth of her child and her age at marriage. This is generally known as the age-specific marital fertility rate. If we are dealing with a Malthusian population, it is preferable, in choosing the sample to be studied, to take into consideration the age at marriage rather than the age at the childs birth. Thus, while the age at birth is sufficient for natural populations, these techniques cannot be applied indiscriminately to all populations.

Family histories. Fertility rates can also be calculated on the basis of family histories, which can be reconstructed from such sources as parish registries (Fleury & Henry 1965) or, in some countries, from systematic family registrations (for instance, the Japanese koseki or honseki). The method for computing the fertility rate for, say, the 25-29-year-old age group from this kind of data is first to determine the number of legitimate births in the group. It is then necessary to make a rigorous count of the number of years lived in wedlock between their 25th and 30th birthdays by all the women in the group; this quantity is known as the groups total woman-years. The number of births is then divided by the number of woman-years to obtain the groups fertility rate. This method is very useful in the study of historical problems in genetics, since it is often the only one that can be applied to the available data.

Let us leavefer tility rates in order to examine rates of reproduction. Here we return to more purely genetic considerations, since we are looking for the mechanism whereby one generation is replaced by the one that follows it. Starting with a series of fertility rates by age groups, a gross reproduction rate can be calculated that gives the average number of female progeny that would be born to an age cohort of women, all of whom live through their entire reproductive period and continue to give birth at the rates prevalent when they themselves were born. The gross reproduction rate obtaining for a population at any one time can be derived by combining the rates for the different age cohorts.

A gross reproduction rate for a real generation can also be determined by calculating the average number of live female children ever born to women of fifty or over. As explained above, this rate is higher for non-Malthusian than for Malthusian populations and can be refined by taking into consideration the length of marriage.

We have seen that in order to be correct, it is necessary for the description of fertility in Malthusian populations to be closely related to the date of marriage. Actually, when a family reaches the size that the parents prefer, fertility tends to approach zero. The preferred size is evidently related to length of marriage in such a manner that fertility is more closely linked with length of marriage than with age at marriage. In recent years great progress has been made in the demographic analysis of fertility, based on this kind of data. This should en ablegeneticists to be more circumspect in their choice of sections of the population to be studied.

Americans talk of cohort analysis, the French of analysis by promotion (a term meaning year or class, as we might speak of the class of 1955). A cohort, or promotion, includes all women born within a 12-month period; to estimate fertility or mortality, it is supposed that these women are all born at the same moment on the first of January of that year. Thus, women born between January 1, 1900, and January 1, 1901, are considered to be exactly 15 years old on January 1, 1915; exactly 47 years old on January 1, 1947; and so forth.

The research done along these lines has issued in the construction of tables that are extremely useful in estimating fertility in a human population. As we have seen, it is more useful to draw up cohorts based on age at marriage than on age at birth. A fertility table set up in this way gives for each cohort the cumulative birth rate, by order of birth and single age of mother, for every woman surviving at each age, from 15 to 49. The progress that population genetics could make in knowing real genie frequencies can be imagined, if it could concentrate its research on any particular cohort and its descendants.

This rapid examination of the facts that demography can now provide in connection with fertility clearly reveals the variables that population genetics can use to make its models coincide with reality. The models retain their validity for genetics because they are still derived from basic genetic concepts; their application to actual problems, however, should be based on the kind of data mentioned above. We have voluntarily limited ourselves to the problem of fertility, since it is the most important factor in genetics research.

The close relationship between demography and population genetics that now appears can be illustrated by the field of research into blood groups. Although researchers concede that blood groups are independent of both age and sex, they do not explore the full consequences of this, since their measures are applied to samples of the population that are representative only in a demographic sense. We must deplore the fact that this method has spread to the other branches of genetics, since it is open to criticism not only from the demographic but from the genetic point of view. By proceeding in this way, a most important factor is overlookedthat of genie frequencies.

Let us admit that the choice of a blood group to be studied is of little impor tance when the characteristic is widely distributed throughout the populationfor instance, if each individual is the carrier of a gene taken into account in the system being studied (e.g., a system made up of groups A, B, and O). But this is no longer the case if the gene is carried only by a few individualsin other words, if its frequency attains 0.1 per cent or less. In this case (and cases like this are common in human genetics) the structure of the sample examined begins to take on prime importance.

A brief example must serve to illustrate this cardinal point. We have seen that in the case of rare recessive genes the importance of consan guineous marriages is considerable. The scarcer that carriers of recessive genes become in the pop ulation as a whole, the greater the proportion of such carriers produced by consanguineous marriages. Thus if as many as 25 per cent of all individuals in a population are carriers of recessive genes, and if one per cent of all marriages in that population are marriages between first cousins, then this one per cent of consanguineous unions will produce 1.12 times as many carriers of recessive genes as will be produced by all the unions of persons not so related. But if recessive genes are carried by only one per cent of the total population, then the same proportion of marriages between first cousins will produce 2.13 times as many carriers as will be produced by all other marriages. This production ratio increases to 4.9 if the total frequency of carriers is .01 per cent, to 20.2 if it is .005 per cent, and to 226 if it is .0001 per cent. Under these conditions, one can see the importance of the sampling method used to estimate the frequency within a population, not only of the individuals who are carriers but of the gametes and genes themselves.

Genealogical method. It should be emphasized that genetic studies based on genealogies remain the least controversial. Studying a population where the degrees of relationship connecting individuals are known presents an obvious interest. Knowing one or several characteristics of certain parents, we can follow what becomes of these in the descendants. Their evolution can also be considered from the point of view of such properties of genes as dominance, recessiveness, expressivity, and penetrance. But above all, we can follow the evolution of these characteristics in the population over time and thus observe the effects of differential fertility. Until now the genealogical method was applicable only to a numerically sparse population, but progress in electronic methods of data processing permits us to anticipate its application to much larger populations (Sutter & Tabah 1956).

Dynamic studies. In very large modern populations it would appear that internal analysis of cohorts and their descendants will bring in the future a large measure of certainty to research in population genetics. In any case, it is a sure way to a dynamic genetics based on demographic reality. For instance, it has been recommended that blood groups should be studied according to age groups; but if we proceed to do so without regard for demographic factors, we cannot make our observations dynamic. Thus, a study that limits itself to, let us say, the fifty- to sixty-year-old age group will have to deal with a universe that includes certain genetically dead elements, such as unmarried and sterile persons, which have no meaning from the dynamic point of view. But if a study is made of this same fifty- to sixty-year-old age group and then of the twenty- to thirty-year-old age group, and if in the older group only those individuals are considered who have descendants in the younger group, the dynamic potential of the data is maximized. It is quite possible to subject demographic cohorts to this sort of interpretation, because in many countries demographic statistics supply series of individuals classified according to the mothers age at their birth.

This discussion would not be complete if we did not stress another aspect of the genetic importance of certain demographic factors, revealed by modern techniques, which have truly created a demographic biology. Particularly worthy of note are the mothers age, order of birth, spacing between births, and size of family.

The mothers age is a great influence on fecundity. A certain number of couples become in capable of having a second child after the birth of the first child; a third child after the second; a fourth after the third; and so forth. This sterility increases with the length of a marriage and especially after the age of 35. It is very important to realize this when, for instance, natural selection and its effects are being studied.

The mothers age also strongly influences the frequency of twin births (monozygotic or dizygotic), spontaneous abortions, stillborn or abnormal births, and so on. Many examples can also be given of the influence of the order of birth, the interval between births, and the size of the family to illustrate their effect on such things as fertility, mortality, morbidity, and malformations.

It has been demonstrated above how seriously demographic factors must be taken into consideration when we wish to study the influence of the genetic structure of populations. We will leave aside the possible environmental influences, such as social class and marital status, since they have previously been codified by Osborn (1956/1957) and Larsson (19561957), among others. At the practical level, however, the continuing efforts to utilize vital statistics for genetic purposes should be pointed out. In this connection, the research of H. B. Newcombe and his colleagues (1965), who are attempting to organize Canadian national statistics for use in genetics, cannot be too highly praised. The United Nations itself posed the problem on the world level at a seminar organized in Geneva in 1960. The question of the relation between demography and genetics is therefore being posed in an acute form.

These problems also impinge in an important way on more general philosophical issues, as has been demonstrated by Haldane (1932), Fisher (1930), and Wright (1951). It must be recognized, however, that their form of Neo-Darwinism, although it is based on Mendelian genetics, too often neglects demographic considerations. In the future these seminal developments should be renewed in full confrontation with demographic reality.

Jean Sutter

[Directly related are the entriesCohort Analysis; Fertility; Fertility Control. Other relevant ma terial may be found inNuptiality; Race; SocialBehavior, Animal, article onThe Regulation of Animal Populations.]

Barclay, George W. 1958 Techniques of Population Analysis. New York: Wiley.

Dahlberg, Gunnar(1943)1948 Mathematical Methods for Population Genetics. New York and London: Inter-science. First published in German.

Dunn, Leslie C. (editor) 1951 Genetics in the Twentieth Century: Essays on the Progress of Genetics During Its First Fifty Years. New York: Macmillan.

Fisher, R. A. (1930) 1958 The Genetical Theory of Natural Selection. 2d ed., rev. New York: Dover.

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Tour of Basic Genetics

What are Traits?

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Get to know the molecule that holds the instructions for building every living thing.

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Learn how traits pass from parents to offspring.

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Take a look at how variation occurs.

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To read a set of chromosomes, scientists look for key features to identify their similarities and differences.

Make a Karyotype

Try your hand at organizing a profile of human chromosomes.

Using Karyotypes To Diagnose Genetic Disorders

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Are Telomeres The Key To Aging And Cancer?

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The terms dominant and recessive describe the inheritance patterns of certain traits. But what do they really mean?

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Compare the two ways for organisms to pass genetic information to their offspring.

The 4 Types of DNA and Molecular Genealogy

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Types of Proteins

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Transcribe and Translate a Gene

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Prions

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Anatomy of a Gene

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Things You May Not KNow About DNA

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PTC: The Genetics of Bitter Taste

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Genes and Blood Type

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The Time of Our Lives

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Basic Genetics

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The genetics of skin cancer is an extremely broad topic. There are more than 100 types of tumors that are clinically apparent on the skin; many of these are known to have familial components, either in isolation or as part of a syndrome with other features. This is, in part, because the skin itself is a complex organ made up of multiple cell types. Furthermore, many of these cell types can undergo malignant transformation at various points in their differentiation, leading to tumors with distinct histology and dramatically different biological behaviors, such as squamous cell carcinoma (SCC) and basal cell cancer (BCC). These have been called nonmelanoma skin cancers or keratinocyte cancers.

Figure 1 is a simple diagram of normal skin structure. It also indicates the major cell types that are normally found in each compartment. Broadly speaking, there are two large compartmentsthe avascular epidermis and the vascular dermiswith many cell types distributed in a largely acellular matrix.[1]

Figure 1. Schematic representation of normal skin. The relatively avascular epidermis houses basal cell keratinocytes and squamous epithelial keratinocytes, the source cells for BCC and SCC, respectively. Melanocytes are also present in normal skin and serve as the source cell for melanoma. The separation between epidermis and dermis occurs at the basement membrane zone, located just inferior to the basal cell keratinocytes.

The outer layer or epidermis is made primarily of keratinocytes but has several other minor cell populations. The bottom layer is formed of basal keratinocytes abutting the basement membrane. The basement membrane is formed from products of keratinocytes and dermal fibroblasts, such as collagen and laminin, and is an important anatomical and functional structure. Basal keratinocytes lose contact with the basement membrane as they divide. As basal keratinocytes migrate toward the skin surface, they progressively differentiate to form the spinous cell layer; the granular cell layer; and the keratinized outer layer, or stratum corneum.

The true cytologic origin of BCC remains in question. BCC and basal cell keratinocytes share many histologic similarities, as is reflected in the name. Alternatively, the outer root sheath cells of the hair follicle have also been proposed as the cell of origin for BCC.[2] This is suggested by the fact that BCCs occur predominantly on hair-bearing skin. BCCs rarely metastasize but can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name "rodent ulcer."[3]

Some debate remains about the origin of SCC; however, these cancers are likely derived from epidermal stem cells associated with the hair follicle.[4] A variety of tissues, such as lung and uterine cervix, can give rise to SCC, and this cancer has somewhat differing behavior depending on its source. Even in cancer derived from the skin, SCC from different anatomic locations can have moderately differing aggressiveness; for example, SCC from glabrous (smooth, hairless) skin has a lower metastatic rate than SCC arising from the vermillion border of the lip or from scars.[3]

Additionally, in the epidermal compartment, melanocytes distribute singly along the basement membrane and can undergo malignant transformation into melanoma. Melanocytes are derived from neural crest cells and migrate to the epidermal compartment near the eighth week of gestational age. Langerhans cells, or dendritic cells, are another cell type in the epidermis and have a primary function of antigen presentation. These cells reside in the skin for an extended time and respond to different stimuli, such as ultraviolet radiation or topical steroids, which cause them to migrate out of the skin.[5]

The dermis is largely composed of an extracellular matrix. Prominent cell types in this compartment are fibroblasts, endothelial cells, and transient immune system cells. When transformed, fibroblasts form fibrosarcomas and endothelial cells form angiosarcomas, Kaposi sarcoma, and other vascular tumors. There are a number of immune cell types that move in and out of the skin to blood vessels and lymphatics; these include mast cells, lymphocytes, mononuclear cells, histiocytes, and granulocytes. These cells can increase in number in inflammatory diseases and can form tumors within the skin. For example, urticaria pigmentosa is a condition that arises from mast cells and is occasionally associated with mast cell leukemia; cutaneous T-cell lymphoma is often confined to the skin throughout its course. Overall, 10% of leukemias and lymphomas have prominent expression in the skin.[6]

Epidermal appendages are also found in the dermal compartment. These are derivatives of the epidermal keratinocytes, such as hair follicles, sweat glands, and the sebaceous glands associated with the hair follicles. These structures are generally formed in the first and second trimesters of fetal development. These can form a large variety of benign or malignant tumors with diverse biological behaviors. Several of these tumors are associated with familial syndromes. Overall, there are dozens of different histological subtypes of these tumors associated with individual components of the adnexal structures.[7]

Finally, the subcutis is a layer that extends below the dermis with varying depth, depending on the anatomic location. This deeper boundary can include muscle, fascia, bone, or cartilage. The subcutis can be affected by inflammatory conditions such as panniculitis and malignancies such as liposarcoma.[8]

These compartments give rise to their own malignancies but are also the region of immediate adjacent spread of localized skin cancers from other compartments. The boundaries of each skin compartment are used to define the staging of skin cancers. For example, an in situ melanoma is confined to the epidermis. Once the cancer crosses the basement membrane into the dermis, it is invasive. Internal malignancies also commonly metastasize to the skin. The dermis and subcutis are the most common locations, but the epidermis can also be involved in conditions such as Pagetoid breast cancer.

The skin has a wide variety of functions. First, the skin is an important barrier preventing extensive water and temperature loss and providing protection against minor abrasions. These functions can be aberrantly regulated in cancer. For example, in the erythroderma (reddening of the skin) associated with advanced cutaneous T-cell lymphoma, alterations in the regulations of body temperature can result in profound heat loss. Second, the skin has important adaptive and innate immunity functions. In adaptive immunity, antigen-presenting cells engender T-cell responses consisting of increased levels of TH1, TH2, or TH17 cells.[9] In innate immunity, the immune system produces numerous peptides with antibacterial and antifungal capacity. Consequently, even small breaks in the skin can lead to infection. The skin-associated lymphoid tissue is one of the largest arms of the immune system. It may also be important in immune surveillance against cancer. Immunosuppression, which occurs during organ transplant, is a significant risk factor for skin cancer. The skin is significant for communication through facial expression and hand movements. Unfortunately, areas of specialized function, such as the area around the eyes and ears, are common places for cancer to occur. Even small cancers in these areas can lead to reconstructive challenges and have significant cosmetic and social ramifications.[1]

While the appearance of any one skin cancer can vary, there are general physical presentations that can be used in screening. BCCs most commonly have a pearly rim or can appear somewhat eczematous (see Figure 2 and Figure 3). They often ulcerate (see Figure 2). SCCs frequently have a thick keratin top layer (see Figure 4). Both BCCs and SCCs are associated with a history of sun-damaged skin. Melanomas are characterized by asymmetry, border irregularity, color variation, a diameter of more than 6 mm, and evolution (ABCDE criteria). (Refer to What Does Melanoma Look Like? on NCI's website for more information about the ABCDE criteria.) Photographs representing typical clinical presentations of these cancers are shown below.

Enlarge

Figure 2. Ulcerated basal cell carcinoma (left panel) and ulcerated basal cell carcinoma with characteristic pearly rim (right panel).

Figure 3. Superficial basal cell carcinoma (left panel) and nodular basal cell carcinoma (right panel).

Enlarge

Figure 4. Squamous cell carcinoma on the face with thick keratin top layer (left panel) and squamous cell carcinoma on the leg (right panel).

Enlarge

Figure 5. Melanomas with characteristic asymmetry, border irregularity, color variation, and large diameter.

Basal cell carcinoma (BCC) is the most common malignancy in people of European descent, with an associated lifetime risk of 30%.[1] While exposure to ultraviolet (UV) radiation is the risk factor most closely linked to the development of BCC, other environmental factors (such as ionizing radiation, chronic arsenic ingestion, and immunosuppression) and genetic factors (such as family history, skin type, and genetic syndromes) also potentially contribute to carcinogenesis. In contrast to melanoma, metastatic spread of BCC is very rare and typically arises from large tumors that have evaded medical treatment for extended periods of time. BCCs can invade tissue locally or regionally, sometimes following along nerves. A tendency for superficial necrosis has resulted in the name "rodent ulcer." With early detection, the prognosis for BCC is excellent.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types. There are different patterns of sun exposure associated with each major type of skin cancer (BCC, squamous cell carcinoma [SCC], and melanoma). (Refer to the PDQ summary on Skin Cancer Prevention for more information about risk factors for skin cancer in the general population.)

The high-risk phenotype consists of individuals with the following physical characteristics:

Specifically, people with more highly pigmented skin demonstrate lower incidence of BCC than do people with lighter pigmented skin. Individuals with Fitzpatrick Type I or II skin were shown to have a twofold increased risk of BCC in a small case-control study.[2] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) Blond or red hair color was associated with increased risk of BCC in two large cohorts: the Nurses Health Study and the Health Professionals Follow-Up Study.[3]

Individuals with BCCs and/or SCCs report a higher frequency of these cancers in their family members than do controls. The importance of this finding is unclear. Apart from defined genetic disorders with an increased risk of BCC, a positive family history of any skin cancer is a strong predictor of the development of BCC.

A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that nonmelanoma skin cancers (NMSCs) have a heritability of 43% (95% confidence interval [CI], 26%59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[4] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.82.0).[4]

A personal history of BCC or SCC is strongly associated with subsequent BCC or SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the mid-60s.[5-10] In addition, several studies have found that individuals with a history of skin cancer have an increased risk of a subsequent diagnosis of a noncutaneous cancer;[11-14] however, other studies have contradicted this finding.[15-18] In the absence of other risk factors or evidence of a defined cancer susceptibility syndrome, as discussed below, skin cancer patients are encouraged to follow screening recommendations for the general population for sites other than the skin.

Mutations in the gene coding for the transmembrane receptor protein PTCH1, or PTCH, are associated with basal cell nevus syndrome (BCNS) and sporadic cutaneous BCCs. (Refer to the BCNS section of this summary for more information.) PTCH1, the human homolog of the Drosophila segment polarity gene patched (ptc), is an integral component of the hedgehog signaling pathway, which serves many developmental (appendage development, embryonic segmentation, neural tube differentiation) and regulatory (maintenance of stem cells) roles.

In the resting state, the transmembrane receptor protein PTCH1 acts catalytically to suppress the seven-transmembrane protein Smoothened (Smo), preventing further downstream signal transduction.[19] Binding of the hedgehog ligand to PTCH1 releases inhibition of Smo, with resultant activation of transcription factors (GLI1, GLI2), cell proliferation genes (cyclin D, cyclin E, myc), and regulators of angiogenesis.[20,21] Thus, the balance of PTCH1 (inhibition) and Smo (activation) manages the essential regulatory downstream hedgehog signal transduction pathway. Loss-of-function mutations of PTCH1 or gain-of-function mutations of Smo tip this balance toward activation, a key event in potential neoplastic transformation.

Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[22,23] Further investigation identified a mutation in PTCH1 that localized to the area of allelic loss.[24] Up to 30% of sporadic BCCs demonstrate PTCH1 mutations.[25] In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other tumors, have been associated with PTCH1 mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH1 mutations, predominantly truncation in type.[26]

Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, have been demonstrated in both BCC and medulloblastoma.[27,28] PTCH2 displays 57% homology to PTCH1.[29] While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[27,30]

BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid BCC syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals.[31] The syndrome is notable for complete penetrance and high levels of variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[26,32] The clinical features of BCNS differ more among families than within families.[33] BCNS is primarily associated with germline mutations in PTCH1, but families with this phenotype have also been associated with alterations in PTCH2 and SUFU.[34-36]

As detailed above, PTCH1 provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH1 in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53.[31] The resulting haploinsufficiency of PTCH1 in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH1.[37] The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH1 mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[38-42] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.[43]

The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (refer to Table 1 for a comparison of these criteria).[44-47] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. The BCNS Colloquium Group proposed criteria in 2011 that required 1 major criterion with molecular diagnosis, two major criteria without molecular diagnosis, or one major and two minor criteria without molecular diagnosis.[47] PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[48,49] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[41,45,50] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.[51] Ameloblastomas, aggressive tumors of the odontogenic epithelium, have also been proposed as a diagnostic criterion for BCNS, but most groups do not include it at this time.[52]

Other associated benign neoplasms include gastric hamartomatous polyps,[53] congenital pulmonary cysts,[54] cardiac fibromas,[55] meningiomas,[56-58] craniopharyngiomas,[59] fetal rhabdomyomas,[60] leiomyomas,[61] mesenchymomas,[62] and nasal dermoid tumors. Development of meningiomas and ependymomas occurring postradiation therapy has been documented in the general pediatric population; radiation therapy for syndrome-associated intracranial processes may be partially responsible for a subset of these benign tumors in individuals with BCNS.[63-65] In addition, radiation therapy of malignant medulloblastomas in the BCNS population may result in many cutaneous BCCs in the radiation ports. Similarly, treatment of BCC of the skin with radiation therapy may result in induction of large numbers of additional BCCs.[40,41,61]

The diagnostic criteria for BCNS are described in Table 1 below.

Of greatest concern with BCNS are associated malignant neoplasms, the most common of which is BCC. BCC in individuals with BCNS may appear during childhood as small acrochordon -like lesions, while larger lesions demonstrate more classic cutaneous features.[66] Nonpigmented BCCs are more common than pigmented lesions.[67] The age at first BCC diagnosis associated with BCNS ranges from 3 to 53 years, with a mean age of 21.4 years; the vast majority of individuals are diagnosed with their first BCC before age 20 years.[45,50] Most BCCs are located on sun-exposed sites, but individuals with greater than 100 BCCs have a more uniform distribution of BCCs over the body.[67] Case series have suggested that up to 1 in 200 individuals with BCC demonstrate findings supportive of a diagnosis of BCNS.[31] BCNS has rarely been reported in individuals with darker skin pigmentation; however, significantly fewer BCCs are found in individuals of African or Mediterranean ancestry.[45,68,69] Despite the rarity of BCC in this population, reported cases document full expression of the noncutaneous manifestations of BCNS.[69] However, in individuals of African ancestry who have received radiation therapy, significant basal cell tumor burden has been reported within the radiation port distribution.[45,61] Thus, cutaneous pigmentation may protect against the mutagenic effects of UV but not against ionizing radiation.

Variants associated with an increased risk of BCC in the general population appear to modify the age of BCC onset in individuals with BCNS. A study of 125 individuals with BCNS found that a variant in MC1R (Arg151Cys) was associated with an early median age of onset of 27 years (95% CI, 2034), compared with individuals who did not carry the risk allele and had a median age of BCC of 34 years (95% CI, 3040) (hazard ratio [HR], 1.64; 95% CI, 1.042.58, P = .034). A variant in the TERT-CLPTM1L gene showed a similar effect, with individuals with the risk allele having a median age of BCC of 31 years (95% CI, 2837) relative to a median onset of 41 years (95% CI, 3248) in individuals who did not carry a risk allele (HR, 1.44; 95% CI, 1.081.93, P = .014).[70]

Many other malignancies have been associated with BCNS. Medulloblastoma carries the strongest association with BCNS and is diagnosed in 1% to 5% of BCNS cases. While BCNS-associated medulloblastoma is typically diagnosed between ages 2 and 3 years, sporadic medulloblastoma is usually diagnosed later in childhood, between the ages of 6 and 10 years.[41,45,50,71] A desmoplastic phenotype occurring around age 2 years is very strongly associated with BCNS and carries a more favorable prognosis than sporadic classic medulloblastoma.[72,73] Up to three times more males than females with BCNS are diagnosed with medulloblastoma.[74] As with other malignancies, treatment of medulloblastoma with ionizing radiation has resulted in numerous BCCs within the radiation field.[41,56] Other reported malignancies include ovarian carcinoma,[75] ovarian fibrosarcoma,[76,77] astrocytoma,[78] melanoma,[79] Hodgkin disease,[80,81] rhabdomyosarcoma,[82] and undifferentiated sinonasal carcinoma.[83]

Odontogenic keratocystsor keratocystic odontogenic tumors (KCOTs), as renamed by the World Health Organization working groupare one of the major features of BCNS.[84] Demonstration of clonal loss of heterozygosity (LOH) of common tumor suppressor genes, including PTCH1, supports the transition of terminology to reflect a neoplastic process.[37] Less than one-half of KCOTs from individuals with BCNS show LOH of PTCH1.[43,85] The tumors are lined with a thin squamous epithelium and a thin corrugated layer of parakeratin. Increased mitotic activity in the tumor epithelium and potential budding of the basal layer with formation of daughter cysts within the tumor wall may be responsible for the high rates of recurrence post simple enucleation.[84,86] In a recent case series of 183 consecutively excised KCOTs, 6% of individuals demonstrated an association with BCNS.[84] A study that analyzed the rate of PTCH1 mutations in BCNS-associated KCOTs found that 11 of 17 individuals carried a germline PTCH1 mutation and an additional 3 individuals had somatic mutations in this gene.[87] Individuals with germline PTCH1 mutations had an early age of KCOT presentation. KCOTs occur in 65% to 100% of individuals with BCNS,[45,88] with higher rates of occurrence in young females.[89]

Palmoplantar pits are another major finding in BCC and occur in 70% to 80% of individuals with BCNS.[50] When these pits occur together with early-onset BCC and/or KCOTs, they are considered diagnostic for BCNS.[90]

Several characteristic radiologic findings have been associated with BCNS, including lamellar calcification of falx cerebri;[91,92] fused, splayed or bifid ribs;[93] and flame-shaped lucencies or pseudocystic bone lesions of the phalanges, carpal, tarsal, long bones, pelvis, and calvaria.[49] Imaging for rib abnormalities may be useful in establishing the diagnosis in younger children, who may have not yet fully manifested a diagnostic array on physical examination.

Table 2 summarizes the frequency and median age of onset of nonmalignant findings associated with BCNS.

Individuals with PTCH2 mutations may have a milder phenotype of BCNS than those with PTCH1 mutations. Characteristic features such as palmar/plantar pits, macrocephaly, falx calcification, hypertelorism, and coarse face may be absent in these individuals.[94]

A 9p22.3 microdeletion syndrome that includes the PTCH1 locus has been described in ten children.[95] All patients had facial features typical of BCNS, including a broad forehead, but they had other features variably including craniosynostosis, hydrocephalus, macrosomia, and developmental delay. At the time of the report, none had basal cell skin cancer. On the basis of their hemizygosity of the PTCH1 gene, these patients are presumably at an increased risk of basal cell skin cancer.

Germline mutations in SUFU, a major negative regulator of the hedgehog pathway, have been identified in a small number of individuals with a clinical phenotype resembling that of BCNS.[35,36] These mutations were first identified in individuals with childhood medulloblastoma,[96] and the incidence of medulloblastoma appears to be much higher in individuals with BCNS associated with SUFU mutations than in those with PTCH1 mutations.[35] SUFU mutations may also be associated with an increased predisposition to meningioma.[58,97] Conversely, odontogenic jaw keratocysts appear less frequently in this population. Some clinical laboratories offer genetic testing for SUFU mutations for individuals with BCNS who do not have an identifiable PTCH1 mutation.

Rombo syndrome, a very rare probably autosomal dominant genetic disorder associated with BCC, has been outlined in three case series in the literature.[98-100] The cutaneous examination is within normal limits until age 7 to 10 years, with the development of distinctive cyanotic erythema of the lips, hands, and feet and early atrophoderma vermiculatum of the cheeks, with variable involvement of the elbows and dorsal hands and feet.[98] Development of BCC occurs in the fourth decade.[98] A distinctive grainy texture to the skin, secondary to interspersed small, yellowish, follicular-based papules and follicular atrophy, has been described.[98,100] Missing, irregularly distributed and/or misdirected eyelashes and eyebrows are another associated finding.[98,99] The genetic basis of Rombo syndrome is not known.

Bazex-Dupr-Christol syndrome, another rare genodermatosis associated with development of BCC, has more thorough documentation in the literature than Rombo syndrome. Inheritance is accomplished in an X-linked dominant fashion, with no reported male-to-male transmission.[101-103] Regional assignment of the locus of interest to chromosome Xq24-q27 is associated with a maximum LOD score of 5.26 with the DXS1192 locus.[104] Further work has narrowed the potential location to an 11.4-Mb interval on chromosome Xq25-27; however, the causative gene remains unknown.[105]

Characteristic physical findings include hypotrichosis, hypohidrosis, milia, follicular atrophoderma of the cheeks, and multiple BCC, which manifest in the late second decade to early third decade.[101] Documented hair changes with Bazex-Dupr-Christol syndrome include reduced density of scalp and body hair, decreased melanization,[106] a twisted/flattened appearance of the hair shaft on electron microscopy,[107] and increased hair shaft diameter on polarizing light microscopy.[103] The milia, which may be quite distinctive in childhood, have been reported to regress or diminish substantially at puberty.[103] Other reported findings in association with this syndrome include trichoepitheliomas; hidradenitis suppurativa; hypoplastic alae; and a prominent columella, the fleshy terminal portion of the nasal septum.[108,109]

A rare subtype of epidermolysis bullosa simplex (EBS), Dowling-Meara (EBS-DM), is primarily inherited in an autosomal dominant fashion and is associated with mutations in either keratin-5 (KRT5) or keratin-14 (KRT14).[110] EBS-DM is one of the most severe types of EBS and occasionally results in mortality in early childhood.[111] One report cites an incidence of BCC of 44% by age 55 years in this population.[112] Individuals who inherit two EBS mutations may present with a more severe phenotype.[113] Other less phenotypically severe subtypes of EBS can also be caused by mutations in either KRT5 or KRT14.[110] Approximately 75% of individuals with a clinical diagnosis of EBS (regardless of subtype) have KRT5 or KRT14 mutations.[114]

Characteristics of hereditary syndromes associated with a predisposition to BCC are described in Table 3 below.

(Refer to the Brooke-Spiegler Syndrome, Multiple Familial Trichoepithelioma, and Familial Cylindromatosis section in the Rare Skin Cancer Syndromes section of this summary for more information about Brooke-Spiegler syndrome.)

As detailed further below, the U.S. Preventive Services Task Force does not recommend regular screening for the early detection of any cutaneous malignancies, including BCC. However, once BCC is detected, the National Comprehensive Cancer Network guidelines of care for NMSCs recommends complete skin examinations every 6 to 12 months for life.[125]

The BCNS Colloquium Group has proposed guidelines for the surveillance of individuals with BCNS (see Table 4).

Level of evidence: 5

Avoidance of excessive cumulative and sporadic sun exposure is important in reducing the risk of BCC, along with other cutaneous malignancies. Scheduling activities outside of the peak hours of UV radiation, utilizing sun-protective clothing and hats, using sunscreen liberally, and strictly avoiding tanning beds are all reasonable steps towards minimizing future risk of skin cancer.[126] For patients with particular genetic susceptibility (such as BCNS), avoidance or minimization of ionizing radiation is essential to reducing future tumor burden.

Level of evidence: 2aii

The role of various systemic retinoids, including isotretinoin and acitretin, has been explored in the chemoprevention and treatment of multiple BCCs, particularly in BCNS patients. In one study of isotretinoin use in 12 patients with multiple BCCs, including 5 patients with BCNS, tumor regression was noted, with decreasing efficacy as the tumor diameter increased.[127] However, the results were insufficient to recommend use of systemic retinoids for treatment of BCC. Three additional patients, including one with BCNS, were followed long-term for evaluation of chemoprevention with isotretinoin, demonstrating significant decrease in the number of tumors per year during treatment.[127] Although the rate of tumor development tends to increase sharply upon discontinuation of systemic retinoid therapy, in some patients the rate remains lower than their pretreatment rate, allowing better management and control of their cutaneous malignancies.[127-129] In summary, the use of systemic retinoids for chemoprevention of BCC is reasonable in high-risk patients, including patients with xeroderma pigmentosum, as discussed in the Squamous Cell Carcinoma section of this summary.

A patients cumulative and evolving tumor load should be evaluated carefully in light of the potential long-term use of a medication class with cumulative and idiosyncratic side effects. Given the possible side-effect profile, systemic retinoid use is best managed by a practitioner with particular expertise and comfort with the medication class. However, for all potentially childbearing women, strict avoidance of pregnancy during the systemic retinoid courseand for 1 month after completion of isotretinoin and 3 years after completion of acitretinis essential to avoid potentially fatal and devastating fetal malformations.

Level of evidence (retinoids): 2aii

In a phase II study of 41 patients with BCNS, vismodegib (an inhibitor of the hedgehog pathway) has been shown to reduce the per-patient annual rate of new BCCs requiring surgery.[130] Existing BCCs also regressed for these patients during daily treatment with 150 mg of oral vismodegib. While patients treated had visible regression of their tumors, biopsy demonstrated residual microscopic malignancies at the site, and tumors progressed after the discontinuation of the therapy. Adverse effects included taste disturbance, muscle cramps, hair loss, and weight loss and led to discontinuation of the medication in 54% of subjects. Based on the side-effect profile and rate of disease recurrence after discontinuation of the medication, additional study regarding optimal dosing of vismodegib is ongoing.

Level of evidence (vismodegib): 1aii

A phase III, double-blind, placebo-controlled clinical trial evaluated the effects of oral nicotinamide (vitamin B3) in 386 individuals with a history of at least two NMSCs within 5 years before study enrollment.[131] After 12 months of treatment, those taking nicotinamide 500 mg twice daily had a 20% reduction in the incidence of new BCCs (95% CI, 6%39%; P = .12). The rate of new NMSCs was 23% lower in the nicotinamide group (95% CI, 438; P =.02) than in the placebo group. No clinically significant differences in adverse events were observed between the two groups, and there was no evidence of benefit after discontinuation of nicotinamide. Of note, this study was not conducted in a population with an identified genetic predisposition to BCC.

Level of evidence (nicotinamide): 1aii

Treatment of individual BCCs in BCNS is generally the same as for sporadic basal cell cancers. Due to the large number of lesions on some patients, this can present a surgical challenge. Field therapy with imiquimod or photodynamic therapy are attractive options, as they can treat multiple tumors simultaneously.[132,133] However, given the radiosensitivity of patients with BCNS, radiation as a therapeutic option for large tumors should be avoided.[45] There are no randomized trials, but the isolated case reports suggest that field therapy has similar results as in sporadic basal cell cancer, with higher success rates for superficial cancers than for nodular cancers.[132,133]

Consensus guidelines for the use of methylaminolevulinate photodynamic therapy in BCNS recommend that this modality may best be used for superficial BCC of all sizes and for nodular BCC less than 2 mm thick.[134] Monthly therapy with photodynamic therapy may be considered for these patients as clinically indicated.

Level of evidence (imiquimod and photodynamic therapy): 4

Topical treatment with LDE225, a Smoothened agonist, has also been investigated for the treatment of BCC in a small number of patients with BCNS with promising results;[135] however, this medication is not approved in this formulation by the U.S. Food and Drug Administration.

Level of evidence (LDE225): 1

In addition to its effects on the prevention of BCCs in patients with BCNS, vismodegib may also have a palliative effect on KCOTs found in this population. An initial report indicated that the use of GDC-0449, the hedgehog pathway inhibitor now known as vismodegib, resulted in resolution of KCOTs in one patient with BCNS.[136] Another small study found that four of six patients who took 150 mg of vismodegib daily had a reduction in the size of KCOTs.[137] None of the six patients in this study had new KCOTs or an increase in the size of existing KCOTs while being treated, and one patient had a sustained response that lasted 9 months after treatment was discontinued.

Level of evidence (vismodegib): 3diii

Squamous cell carcinoma (SCC) is the second most common type of skin cancer and accounts for approximately 20% of cutaneous malignancies. Although most cancer registries do not include information on the incidence of nonmelanoma skin cancer (NMSC), annual incidence estimates range from 1 million to 5.4 million cases in the United States.[1,2]

Mortality is rare from this cancer; however, the morbidity and costs associated with its treatment are considerable.

Sun exposure is the major known environmental factor associated with the development of skin cancer of all types; however, different patterns of sun exposure are associated with each major type of skin cancer.

Unlike basal cell carcinoma (BCC), SCC is associated with chronic exposure, rather than intermittent intense exposure to ultraviolet (UV) radiation. Occupational exposure is the characteristic pattern of sun exposure linked with SCC.[3] A case-control study in southern Europe showed increased risk of SCC when lifetime sun exposure exceeded 70,000 hours. People whose lifetime sun exposure equaled or exceeded 200,000 hours had an odds ratio (OR) 8 to 9 times that of the reference group.[4] A Canadian case-control study did not find an association between cumulative lifetime sun exposure and SCC; however, sun exposure in the 10 years before diagnosis and occupational exposure were found to be risk factors.[5]

In addition to environmental radiation, exposure to therapeutic radiation is another risk factor for SCC. Individuals with skin disorders treated with psoralen and ultraviolet-A radiation (PUVA) had a threefold to sixfold increase in SCC.[6] This effect appears to be dose-dependent, as only 7% of individuals who underwent fewer than 200 treatments had SCC, compared with more than 50% of those who underwent more than 400 treatments.[7] Therapeutic use of ultraviolet-B (UVB) radiation has also been shown to cause a mild increase in SCC (adjusted incidence rate ratio, 1.37).[8] Devices such as tanning beds also emit UV radiation and have been associated with increased SCC risk, with a reported OR of 2.5 (95% confidence interval [CI], 1.73.8).[9]

Investigation into the effect of ionizing radiation on SCC carcinogenesis has yielded conflicting results. One population-based case-control study found that patients who had undergone therapeutic radiation therapy had an increased risk of SCC at the site of previous radiation (OR, 2.94), compared with individuals who had not undergone radiation treatments.[10] Cohort studies of radiology technicians, atomic-bomb survivors, and survivors of childhood cancers have not shown an increased risk of SCC, although the incidence of BCC was increased in all of these populations.[11-13] For those who develop SCC at previously radiated sites that are not sun-exposed, the latent period appears to be quite long; these cancers may be diagnosed years or even decades after the radiation exposure.[14]

The effect of other types of radiation, such as cosmic radiation, is also controversial. Pilots and flight attendants have a reported incidence of SCC that ranges between 2.1 and 9.9 times what would be expected; however, the overall cancer incidence is not consistently elevated. Some attribute the high rate of NMSCs in airline flight personnel to cosmic radiation, while others suspect lifestyle factors.[15-20]

Like BCCs, SCCs appear to be associated with exposure to arsenic in drinking water and combustion products.[21,22] However, this association may hold true only for the highest levels of arsenic exposure. Individuals who had toenail concentrations of arsenic above the 97th percentile were found to have an approximately twofold increase in SCC risk.[23] For arsenic, the latency period can be lengthy; invasive SCC has been found to develop at an average of 20 years after exposure.[24]

Current or previous cigarette smoking has been associated with a 1.5-fold to 2-fold increase in SCC risk,[25-27] although one large study showed no change in risk.[28] Available evidence suggests that the effect of smoking on cancer risk seems to be greater for SCC than for BCC.

Additional reports have suggested weak associations between SCC and exposure to insecticides, herbicides, or fungicides.[29]

Like melanoma and BCC, SCC occurs more frequently in individuals with lighter skin than in those with darker skin.[3,30] A case-control study of 415 cases and 415 controls showed similar findings; relative to Fitzpatrick Type I skin, individuals with increasingly darker skin had decreased risks of skin cancer (ORs, 0.6, 0.3, and 0.1, for Fitzpatrick Types II, III, and IV, respectively).[31] (Refer to the Pigmentary characteristics section in the Melanoma section of this summary for a more detailed discussion of skin phenotypes based upon pigmentation.) The same study found that blue eyes and blond/red hair were also associated with increased risks of SCC, with crude ORs of 1.7 (95% CI, 1.22.3) for blue eyes, 1.5 (95% CI, 1.12.1) for blond hair, and 2.2 (95% CI, 1.53.3) for red hair.

However, SCC can also occur in individuals with darker skin. An Asian registry based in Singapore reported an increase in skin cancer in that geographic area, with an incidence rate of 8.9 per 100,000 person-years. Incidence of SCC, however, was shown to be on the decline.[30] SCC is the most common form of skin cancer in black individuals in the United States and in certain parts of Africa; the mortality rate for this disease is relatively high in these populations.[32,33] Epidemiologic characteristics of, and prevention strategies for, SCC in those individuals with darker skin remain areas of investigation.

Freckling of the skin and reaction of the skin to sun exposure have been identified as other risk factors for SCC.[34] Individuals with heavy freckling on the forearm were found to have a 14-fold increase in SCC risk if freckling was present in adulthood, and an almost threefold risk if freckling was present in childhood.[34,35] The degree of SCC risk corresponded to the amount of freckling. In this study, the inability of the skin to tan and its propensity to burn were also significantly associated with risk of SCC (OR of 2.9 for severe burn and 3.5 for no tan).

The presence of scars on the skin can also increase the risk of SCC, although the process of carcinogenesis in this setting may take years or even decades. SCCs arising in chronic wounds are referred to as Marjolins ulcers. The mean time for development of carcinoma in these wounds is estimated at 26 years.[36] One case report documents the occurrence of cancer in a wound that was incurred 59 years earlier.[37]

Immunosuppression also contributes to the formation of NMSCs. Among solid-organ transplant recipients, the risk of SCC is 65 to 250 times higher, and the risk of BCC is 10 times higher than that observed in the general population, although the risks vary with transplant type.[38-41] NMSCs in high-risk patients (solid-organ transplant recipients and chronic lymphocytic leukemia patients) occur at a younger age, are more common and more aggressive, and have a higher risk of recurrence and metastatic spread than these cancers do in the general population.[42,43] Additionally, there is a high risk of second SCCs.[44,45] In one study, over 65% of kidney transplant recipients developed subsequent SCCs after their first diagnosis.[44] Among patients with an intact immune system, BCCs outnumber SCCs by a 4:1 ratio; in transplant patients, SCCs outnumber BCCs by a 2:1 ratio.

This increased risk has been linked to an interaction between the level of immunosuppression and UV radiation exposure. As the duration and dosage of immunosuppressive agents increase, so does the risk of cutaneous malignancy; this effect is reversed with decreasing the dosage of, or taking a break from, immunosuppressive agents. Heart transplant recipients, requiring the highest rates of immunosuppression, are at much higher risk of cutaneous malignancy than liver transplant recipients, in whom much lower levels of immunosuppression are needed to avoid rejection.[38,46,47] The risk appears to be highest in geographic areas with high UV exposure.[47] When comparing Australian and Dutch organ transplant populations, the Australian patients carried a fourfold increased risk of developing SCC and a fivefold increased risk of developing BCC.[48] This finding underlines the importance of rigorous sun avoidance, particularly among high-risk immunosuppressed individuals.

Certain immunosuppressive agents have been associated with increased risk of SCC. Kidney transplant patients who received cyclosporine in addition to azathioprine and prednisolone had a 2.8-fold increase in risk of SCC over those kidney transplant patients on azathioprine and prednisolone alone.[38] In cardiac transplant patients, increased incidence of SCC was seen in individuals who had received OKT3 (muromonab-CD3), a murine monoclonal antibody against the CD3 receptor.[49]

A personal history of BCC or SCC is strongly associated with subsequent SCC. A study from Ireland showed that individuals with a history of BCC had a 14% higher incidence of subsequent SCC; for men with a history of BCC, the subsequent SCC risk was 27% higher.[50] In the same report, individuals with melanoma were also 2.5 times more likely to report a subsequent SCC. There is an approximate 20% increased risk of a subsequent lesion within the first year after a skin cancer has been diagnosed. The mean age of occurrence for these NMSCs is the middle of the sixth decade of life.[26,51-55]

A Swedish study of 224 melanoma index cases and 944 of their first-degree relatives (FDRs) from 154 CDKN2A wild-type families and 11,680 matched controls showed that personal and family histories of melanoma increased the risk of SCC, with relative risks (RRs) of 9.1 (95% CI, 6.013.7) for personal history and 3.4 (95% CI, 2.25.2) for family history.[56]

Although the literature is scant on this subject, a family history of SCC may increase the risk of SCC in FDRs. In an independent survey-based study of 415 SCC cases and 415 controls, SCC risk was increased in individuals with a family history of SCC (adjusted OR, 3.4; 95% CI, 1.011.6), even after adjustment for skin type, hair color, and eye color.[31] This risk was elevated to an OR of 5.6 in those with a family history of melanoma (95% CI, 1.619.7), 9.8 in those with a family history of BCC (95% CI, 2.636.8), and 10.5 in those with a family history of multiple types of skin cancer (95% CI, 2.729.6). Review of the Swedish Family Center Database showed that individuals with at least one sibling or parent affected with SCC, in situ SCC (Bowen disease), or actinic keratosis had a twofold to threefold increased risk of invasive and in situ SCC relative to the general population.[57,58] Increased number of tumors in parents was associated with increased risk to the offspring. Of note, diagnosis of the proband at an earlier age was not consistently associated with a trend of increased incidence of SCC in the FDR, as would be expected in most hereditary syndromes because of germline mutations. Further analysis of the Swedish population-based data estimates genetic risk effects of 8% and familial shared-environmental effects of 18%.[59] Thus, shared environmental and behavioral factors likely account for some of the observed familial clustering of SCC.

A study on the heritability of cancer among 80,309 monozygotic and 123,382 dizygotic twins showed that NMSCs have a heritability of 43% (95% CI, 26%59%), suggesting that almost half of the risk of NMSC is caused by inherited factors.[60] Additionally, the cumulative risk of NMSC was 1.9-fold higher for monozygotic than for dizygotic twins (95% CI, 1.82.0).[60]

Major genes have been defined elsewhere in this summary as genes that are necessary and sufficient for disease, with important mutations of the gene as causal. The disorders resulting from single-gene mutations within families lead to a very high risk of disease and are relatively rare. The influence of the environment on the development of disease in individuals with these single-gene disorders is often very difficult to determine because of the rarity of the genetic mutation.

Identification of a strong environmental risk factorchronic exposure to UV radiationmakes it difficult to apply genetic causation for SCC of the skin. Although the risk of UV exposure is well known, quantifying its attributable risk to cancer development has proven challenging. In addition, ascertainment of cases of SCC of the skin is not always straightforward. Many registries and other epidemiologic studies do not fully assess the incidence of SCC of the skin owing to: (1) the common practice of treating lesions suspicious for SCC without a diagnostic biopsy, and (2) the relatively low potential for metastasis. Moreover, NMSC is routinely excluded from the major cancer registries such as the Surveillance, Epidemiology, and End Results registry.

With these considerations in mind, the discussion below will address genes associated with disorders that have an increased incidence of skin cancer.

Characteristics of the major hereditary syndromes associated with a predisposition to SCC are described in Table 5 below.

Xeroderma pigmentosum (XP) is a hereditary disorder of nucleotide excision repair that results in cutaneous malignancies in the first decade of life. Affected individuals have an increased sensitivity to sunlight, resulting in a markedly increased risk of SCCs, BCCs, and melanomas. One report found that NMSC was increased 150-fold in individuals with XP; for those younger than 20 years, the prevalence was almost 5,000 times what would be expected in the general population.[61]

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Genetics of Skin Cancer (PDQ)Health Professional Version ...

Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an ameoba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It's even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, the nitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as it includes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the more familiar "adenine" label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn't a mistake. First, there's less DNA in a sperm cell than there is in a non-reproductive cell such as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that's going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

See the rest here:
Cell Size and Scale - Learn Genetics

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The public health burden of prostate cancer is substantial. A total of 180,890 new cases of prostate cancer and 26,120 deaths from the disease are anticipated in the United States in 2016, making it the most frequent nondermatologic cancer among U.S. males.[1] A mans lifetime risk of prostate cancer is one in seven. Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.[1]

Some men with prostate cancer remain asymptomatic and die from unrelated causes rather than as a result of the cancer itself. This may be due to the advanced age of many men at the time of diagnosis, slow tumor growth, or response to therapy.[2] The estimated number of men with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patients life) is greater than the number of men with clinically detected disease. A better understanding is needed of the genetic and biologic mechanisms that determine why some prostate carcinomas remain clinically silent, while others cause serious, even life-threatening illness.[2]

Prostate cancer exhibits tremendous differences in incidence among populations worldwide; the ratio of countries with high and low rates of prostate cancer ranges from 60-fold to 100-fold.[3] Asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 2 to 10 cases per 100,000 men. Higher incidence rates are generally observed in northern European countries. African American men, however, have the highest incidence of prostate cancer in the world; within the United States, African American men have a 60% higher incidence rate than white men.[4] African American men have been reported to have more than twice the rate of prostate cancerspecific death compared with non-Hispanic white men.[1] Differences in race-specific prostate cancer survival estimates may be narrowing over time.[5]

These differences may be due to the interplay of genetic, environmental, and social influences (such as access to health care), which may affect the development and progression of the disease.[6] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[7] This may account for an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, and there is increasing knowledge of the molecular genetics of the disease, although much of what is known is not yet clinically actionable. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initiation and promotional events under both genetic and environmental influences.[8]

The three most important recognized risk factors for prostate cancer in the United States are:

Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40 years; the incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 325 for men 49 years or younger, 1 in 48 for men aged 50 through 59 years, 1 in 17 for men aged 60 through 69 years, and 1 in 10 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 7.[1]

Approximately 10% of prostate cancer cases are diagnosed in men younger than 56 years and represent early-onset prostate cancer. Data from the Surveillance, Epidemiology, and End Results (SEER) Program show that early-onset prostate cancer is increasing, and there is evidence that some cases may be more aggressive.[9] Because early-onset cancers may result from germline mutations, young men with prostate cancer are being extensively studied with the goal of identifying prostate cancer susceptibility genes.

The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese.[10,11] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[12]

Prostate cancer is highly heritable; the inherited risk of prostate cancer has been estimated to be as high as 60%.[13] As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[14-18] From 5% to 10% of prostate cancer cases are believed to be primarily caused by high-risk inherited genetic factors or prostate cancer susceptibility genes. Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[15,19,20] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[16-20] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.[21]

Although some of the prostate cancer studies examining risks associated with family history have used hospital-based series, several studies described population-based series.[22-24] The latter are thought to provide information that is more generalizable. A meta-analysis of 33 epidemiologic case-control and cohort-based studies has provided more detailed information regarding risk ratios related to family history of prostate cancer. Risk appeared to be greater for men with affected brothers than for men with affected fathers in this meta-analysis. Although the reason for this difference in risk is unknown, possible hypotheses have included X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives. Risk also increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years. (See Table 1 for a summary of the relative risks [RRs] related to a family history of prostate cancer.)[25]

Among the many data sources included in this meta-analysis, those from the Swedish population-based Family-Cancer Database warrant special comment. These data were derived from a resource that contained more than 11.8 million individuals, among whom there were 26,651 men with medically verified prostate cancer, of which 5,623 were familial cases.[26] The size of this data set, with its nearly complete ascertainment of the entire Swedish population and objective verification of cancer diagnoses, should yield risk estimates that are both accurate and free of bias. When the familial age-specific hazard ratios (HRs) for prostate cancer diagnosis and mortality were computed, as expected, the HR for prostate cancer diagnosis increased with more family history. Specifically, HRs for prostate cancer were 2.12 (95% CI, 2.052.20) with an affected father only, 2.96 (95% CI, 2.803.13) with an affected brother only, and 8.51 (95% CI, 6.1311.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.2625.67), was seen in men with three brothers diagnosed with prostate cancer. The HRs were even higher when the affected relative was diagnosed with prostate cancer before age 55 years.

A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5% by age 60 years, 15% by age 70 years, and 30% by age 80 years, compared with 0.45%, 3%, and 10%, respectively, by the same ages in the general population. The risks were even higher when the affected father was diagnosed before age 70 years.[27] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three age groups, respectively, yielding a total PAF of 11.6% (i.e., approximately 11.6% of all prostate cancers in Sweden can be accounted for on the basis of familial history of the disease).

The risk of prostate cancer may also increase in men who have a family history of breast cancer. Approximately 9.6% of the Iowa cohort had a family history of breast and/or ovarian cancer in a mother or sister at baseline, and this was positively associated with prostate cancer risk (age-adjusted RR, 1.7; 95% CI, 1.03.0; multivariate RR, 1.7; 95% CI, 0.93.2). Men with a family history of both prostate and breast/ovarian cancer were also at increased risk of prostate cancer (RR, 5.8; 95% CI, 2.414.0).[22] Analysis of data from the Women's Health Initiative also showed that a family history of prostate cancer was associated with an increase in the risk of postmenopausal breast cancer (adjusted HR, 1.14; 95% CI, 1.021.26).[28] Further analyses showed that breast cancer risk was associated with a family history of both breast and prostate cancers; the risk was higher in black women than in white women. Other studies, however, did not find an association between family history of female breast cancer and risk of prostate cancer.[22,29] A family history of prostate cancer also increases the risk of breast cancer among female relatives.[30] The association between prostate cancer and breast cancer in the same family may be explained, in part, by the increased risk of prostate cancer among men with BRCA1/BRCA2 mutations in the setting of hereditary breast/ovarian cancer or early-onset prostate cancer.[31-34] (Refer to the BRCA1 and BRCA2 section of this summary for more information.)

Prostate cancer clusters with particular intensity in some families. Highly penetrant genetic variants are thought to be associated with prostate cancer risk in these families. (Refer to the Linkage Analyses section of this summary for more information.) Members of such families may benefit from genetic counseling. Emerging recommendations and guidelines for genetic counseling referrals are based on prostate cancer age at diagnosis and specific family cancer history patterns.[35,36] Individuals meeting the following criteria may warrant referral for genetic consultation:[35-38]

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African Americans, whites, and Asian Americans in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[39] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian Americans than among African Americans or whites. A positive family history was associated with a twofold to threefold increase in RR in each of the three ethnic groups. The overall odds ratio associated with a family history of prostate cancer was 2.5 (95% CI, 1.93.3) with adjustment for age and ethnicity.[39]

Endogenous hormones, including both androgens and estrogens, likely influence prostate carcinogenesis. It has been widely reported that eunuchs and other individuals with castrate levels of testosterone before puberty do not develop prostate cancer.[40] Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[41] including the potential role of the androgen receptor (AR) CAG repeat length in exon 1. This modulates AR activity, which may influence prostate cancer risk.[42] For example, a meta-analysis reported that AR CAG repeat length greater than or equal to 20 repeats conferred a protective effect for prostate cancer in subsets of men.[43]

(Refer to the PDQ summary on Prostate Cancer Prevention for more information about nongenetic modifiers of prostate cancer risk in the general population.)

The SEER Cancer Registries assessed the risk of developing a second primary cancer in 292,029 men diagnosed with prostate cancer between 1973 and 2000. Excluding subsequent prostate cancer and adjusting for the risk of death from other causes, the cumulative incidence of a second primary cancer among all patients was 15.2% at 25 years (95% CI, 5.015.4). There was a significant risk of new malignancies (all cancers combined) among men diagnosed before age 50 years, no excess or deficit in cancer risk in men aged 50 to 59 years, and a deficit in cancer risk in all older age groups. The authors suggested that this deficit may be attributable to decreased cancer surveillance in an elderly population. Excess risks of second primary cancers included cancers of the small intestine, soft tissue, bladder, thyroid, and thymus; and melanoma. Prostate cancer diagnosed in patients aged 50 years or younger was associated with an excess risk of pancreatic cancer.[44]

A review of more than 441,000 men diagnosed with prostate cancer between 1992 and 2010 demonstrated similar findings, with an overall reduction in the risk of being diagnosed with a second primary cancer. This study also examined the risk of second primary cancers in 44,310 men (10%) by treatment modality for localized cancer. The study suggested that men who received radiation therapy had increases in bladder (standardized incidence ratio [SIR], 1.42) and rectal cancer risk (SIR, 1.70) compared with those who did not receive radiation therapy (SIRbladder, 0.76; SIRrectal, 0.74).[45]

The underlying etiology of developing a second primary cancer after prostate cancer may be related to various factors, including treatment modality. More than 50% of the small intestine tumors were carcinoid malignancies, suggesting possible hormonal influences. The excess of pancreatic cancer may be due to mutations in BRCA2, which predisposes to both. The risk of melanoma was most pronounced in the first year of follow-up after diagnosis, raising the possibility that this is the result of increased screening and surveillance.[44]

One Swedish study using the nationwide Swedish Family Cancer Database assessed the role of family history in the risk of a second primary cancer after prostate cancer. Of 18,207 men with prostate cancer, 560 developed a second primary malignancy. Of those, the RR was increased for colorectal, kidney, bladder, and squamous cell skin cancers. Having a paternal family history of prostate cancer was associated with an increased risk of bladder cancer, myeloma, and squamous cell skin cancer. Among prostate cancer probands, those with a family history of colorectal cancer, bladder cancer, or chronic lymphoid leukemia were at increased risk of that specific cancer as a second primary cancer.[46]

Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.[47-49]

In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined (other than prostate cancer) was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer (SIR, 1.9; 95% CI, 1.03.2). No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer sitespecific disorder.[50]

Many types of epidemiologic studies (case-control, cohort, twin, family) strongly suggest that prostate cancer susceptibility genes exist in the population. Analysis of longer follow-up of the monozygotic (MZ) and dizygotic (DZ) twin pairs in Scandinavia concluded that 58% (95% CI, 5263) of prostate cancer risk may be accounted for by heritable factors.[13] Additionally, among affected MZ and DZ pairs, the time to diagnosis in the second twin was shortest in MZ twins (mean, 3.8 years in MZ twins vs. 6.5 years in DZ twins). This is in agreement with a previous U.S. study that showed a concordance of 7.1% between DZ twin pairs and a 27% concordance between MZ twin pairs.[51] The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare (frequency of 0.003) autosomal dominant, highly penetrant allele(s).[15] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 years or younger). In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.[52]

Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[53-55] A study of 4,288 men who underwent radical prostatectomy between 1966 and 1995 found that the best fitting genetic model of inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In this study, the lifetime risk in carriers was estimated to be 89% by age 85 years and 3.9% for noncarriers.[51] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in FDRs of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there are multiple genes associated with prostate cancer [56-59] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for Mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (<66 years) than noncarriers. This is the first segregation analysis to show a recessive mode of inheritance.[60]

Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred. Typically, gene mutations identified through linkage analyses are rare in the population, are moderately to highly penetrant in families, and have large (e.g., relative risk >2.0) effect sizes. The clinical role of mutations that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Genes With Potential Clinical Relevance in Prostate Cancer Risk section of this summary for more information about these genes.) Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have low to modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.

The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.

Linkage studies are typically performed on high-risk kindreds in whom multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is affected by the following:

Furthermore, because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[1] One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of hereditary prostate cancer families.[2] Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have hereditary prostate cancer:

Using these criteria, surgical series have reported that approximately 3% to 5% of men will be from a family with hereditary prostate cancer.[2,3]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. Because a mans lifetime risk of prostate cancer is one in seven,[4] it is possible that families under study have men with both inherited and sporadic prostate cancer. Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer. There are no clinical or pathological features of prostate cancer that will allow differentiation between inherited and sporadic forms of the disease, although current advances in the understanding of molecular phenotypes of prostate cancer may be informative in identifying inherited prostate cancer. Similarly, there are limited data regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate loci. Measurement of the serum prostate-specific antigen (PSA) has been used inconsistently in evaluating families used in linkage analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased by the use of serum PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.

One way to address inconsistencies between linkage studies is to require inclusion criteria that define clinically significant disease (e.g., Gleason score 7, PSA 20 ng/mL) in an affected man.[5-7] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]

Table 2 summarizes the proposed prostate cancer susceptibility loci identified in families with multiple prostate canceraffected individuals. Conflicting evidence exists regarding the linkage to some of the loci described above. Data on the proposed phenotype associated with each locus are also limited, and the strength of repeated studies is needed to firmly establish these associations. Evidence suggests that many of these prostate cancer loci account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.

Genome-wide linkage studies of families with prostate cancer have identified several other loci that may harbor prostate cancer susceptibility genes, emphasizing the underlying complexity and genetic heterogeneity of this cancer. The following chromosomal regions have been found to be associated with prostate cancer in more than one study or clinical cohort with a statistically significant (2) logarithm of the odds (LOD) score, heterogeneity LOD (HLOD) score, or summary LOD score:

The chromosomal region 19q has also been found to be associated with prostate cancer, although specific LOD scores have not been described.[8,11,95]

Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint HLOD scores of 1.3 to less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint HLOD score = 1.08) and 22q12 (multipoint HLOD score = 0.91).[92,99] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (HLOD = 1.97) and 12q24 (HLOD = 2.21) using a 6,000 single nucleotide polymorphism (SNP) platform.[111] Further study including a larger number of African American families is needed to confirm these findings.

In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analysis was performed in families with one or more of the following: Gleason grade 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer before age 65 years. One hundred twenty-three families with two or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (HLOD score = 2.18) and 22q12.3-q13.1 (HLOD score = 1.90).[5] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine-mapping study of 14 extended high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[107] An analysis of high-risk pedigrees from Utah provides an overview of this strategy.[112] A linkage analysis utilizing a higher resolution marker set of 6,000 SNPs was performed among 348 families from the International Consortium for Prostate Cancer Genetics with aggressive prostate cancer.[44] Aggressive disease was defined as Gleason score 7 or higher, invasion into seminal vesicles or extracapsular extension, pretreatment PSA level of 20 ng/mL or higher, or death from prostate cancer. The region with strongest evidence of linkage among aggressive prostate cancer families was 8q24 with LOD scores of 3.093.17. Additional regions of linkage included with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.

In light of the multiple prostate cancer susceptibility loci and disease heterogeneity, another approach has been to stratify families based on other cancers, given that many cancer susceptibility genes are pleiotropic.[113] A genome-wide linkage study was conducted to identify a susceptibility locus that may account for both prostate cancer and kidney cancer in families. Analysis of 15 families with evidence of hereditary prostate cancer and one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a man with prostate cancer revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.[114] This observation awaits confirmation. Another genome-wide linkage study was conducted in 96 hereditary prostate cancer families with one or more first-degree relatives with colon cancer. Evidence for linkage in all families was found in several regions, including 11q25, 15q14, and 18q21. In families with two or more cases of colon cancer, linkage was also observed at 1q31, 11q14, and 15q11-14.[113]

Linkage to chromosome 17q21-22 and subsequent fine-mapping and targeted sequencing have identified recurrent mutations in the HOXB13 gene that account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. Multiple studies have confirmed the association between the G84E mutation in HOXB13 and prostate cancer risk. (Refer to the HOXB13 section of this summary for more information.) The clinical utility of testing for HOXB13 mutations has not yet been defined, but studies are ongoing to define the clinical role. For example, a study evaluated 948 unselected men scheduled for prostate biopsy. The G84E mutation was found in three men (0.3%) who had prostate cancer detected on biopsy, although none of the 301 men who had a family history of prostate cancer carried the mutation.[115] Furthermore, many linkage studies have mapped several prostate cancer susceptibility loci (Table 2), although the genetic alterations contributing to hereditary prostate cancer from these loci have not been consistently reproduced. With the evolution of high-throughput sequencing technologies, there will likely be additional moderately to highly penetrant genetic mutations identified to account for subsets of hereditary prostate cancer families.[116]

A case-control study involves evaluating factors of interest for association to a condition. The design involves investigation of cases with a condition of interest, such as a specific disease or gene mutation, compared with a control sample without that condition, but often with other similar characteristics (i.e., age, gender, and ethnicity). Limitations of case-control design with regard to identifying genetic factors include the following:[117,118]

Additionally, identified associations may not always be valid, but they could represent a random association and, therefore, warrant validation studies.[117,118]

Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR is expressed during all stages of prostate carcinogenesis.[120] One study demonstrated that men with hereditary prostate cancer who underwent radical prostatectomy had a higher percentage of prostate cancer cells exhibiting expression of the AR and a lower percentage of cancer cells expressing estrogen receptor alpha than did men with sporadic prostate cancer. The authors suggest that a specific pattern of hormone receptor expression may be associated with hereditary predisposition to prostate cancer.[121]

Altered activity of the AR caused by inherited variants of the AR gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[122,123] Some studies have suggested an inverse association between CAG repeat length and prostate cancer risk, and a direct association between GGN repeat length and risk of prostate cancer; however, the evidence is inconsistent.[120,122-132] A meta-analysis of 19 case-control studies demonstrated a statistically significant association between both short CAG length (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.11.3) and short GGN length (OR, 1.3; 95% CI, 1.11.6) and prostate cancer; however, the absolute difference in number of repeats between cases and controls is less than one, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[133] Subsequently, the large multiethnic cohort study of 2,036 incident prostate cancer cases and 2,160 ethnically matched controls failed to confirm a statistically significant association (OR, 1.02; P = .11) between CAG repeat size and prostate cancer.[134] A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between AR alleles, with more than 22 CAG repeats and prostate cancer (OR, 1.35; 95% CI, 1.081.69; P = .03).[135]

An analysis of AR gene CAG and CGN repeat length polymorphisms targeted African American men from the Flint Mens Health Study in an effort to identify a genetic modifier that might help explain the increased risk of prostate cancer in black versus white males in the United States.[136] This population-based study of 131 African American prostate cancer patients and 340 screened-negative African American controls showed no evidence of an association between shorter AR repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[134,137,138] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African American men.

Germline mutations in the AR gene (located on the X chromosome) have been rarely reported. The R726L mutation has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[139] This mutation, which alters the transactivational specificity of the AR protein, was found in 8 of 418 (1.91%) consecutive sporadic prostate cancer cases, 2 of 106 (1.89%) familial cases, and 3 of 900 (0.33%) normal blood donors, yielding a significantly increased prostate cancer OR of 5.8 for both case groups. A subsequent Finnish study of 38 early-onset prostate cancer cases and 36 multiple-case prostate cancer families with no evidence of male-to-male transmission revealed one additional R726L mutation in one of the familial cases and no new germline mutations in the AR gene.[140] These investigators concluded that germline AR mutations explain only a small fraction of familial and early-onset cases in Finland.

A study of genomic DNA from 60 multiple-case African American (n = 30) and white (n = 30) families identified a novel missense germline AR mutation, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this mutation was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[141]

Molecular epidemiology studies have also examined genetic polymorphisms of the steroid 5-alpha-reductase 2 gene, which is also involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydrotestosterone (DHT) by 5-alpha-reductase type II.[142] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[143,144]

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[145] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[142,146] Although no clinical significance for these polymorphisms has yet been determined, some TA repeat alleles may promote an elevation of enzyme activity, which may in turn increase the level of DHT in the prostate.[120,142] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, although a relationship could not be definitively excluded.[147] This meta-analysis also examined the potential roles of two coding variants: A49T and V89L. An association with V89L was excluded, and the role for A49T was found to have at most a modest effect on prostate cancer susceptibility. Bias or chance could account for the latter observation. A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between two variants in SRD5A2 and prostate cancer risk (OR, 1.45; 95% CI, 1.012.08; OR, 1.49; 95% CI, 1.032.15).[135] Another meta-analysis of 25 case-control studies, including 8,615 cases and 9,089 controls, found no overall association between the V89L polymorphism and prostate cancer risk. In a subgroup analysis, men younger than 65 years (323 cases and 677 controls) who carried the LL genotype had a modest association with prostate cancer (LL vs. VV, OR, 1.70; 95% CI, 1.092.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.142.68).[148] A subsequent systematic review and meta-analysis including 27 nonfamilial case-control studies found no statistically significant association between either the V89L or A49T polymorphisms and prostate cancer risk.[149]

Polymorphisms in several genes involved in the biosynthesis, activation, metabolism, and degradation of androgens (CYP17, CYP3A4, CYP19A1, and SRD5A2) and the stimulation of mitogenic and antiapoptotic activities (IGF-1 and IGFBP-3) of normal prostate cells were examined for association with prostate cancer in 131 African American cases and 342 controls. While allele frequencies did not differ between cases and controls regarding three SNPs in the CYP17 gene (rs6163, rs6162, and rs743572), heterozygous genotypes of these SNPs were found to be associated with a reduced risk (OR, 0.56; 95% CI, 0.350.88; OR, 0.57; 95% CI, 0.360.90; OR, 0.55; 95% CI, 0.350.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.942.63).[150] Additional studies are needed to confirm these findings.

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of SNPs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNP in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[151] This study awaits replication.

Germline mutations in the tumor suppressor gene E-cadherin (also called CDH1) cause a hereditary form of gastric carcinoma. A SNP designated -160A, located in the promoter region of E-cadherin, has been found to alter the transcriptional activity of this gene.[152] Because somatic mutations in E-cadherin have been implicated in the development of invasive malignancies in a number of different cancers,[153] investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 47 case-control studies in 16 cancer types included ten prostate cancer cohorts (3,570 cases and 3,304 controls). The OR of developing prostate cancer among risk allele carriers was 1.33 (95% CI, 1.111.60). However, the authors of the study noted that there are sources of bias in the dataset, stemming mostly from the small sample sizes of individual cohorts.[154] Additional studies are required to determine whether this finding is reproducible and biologically and clinically important.

There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[155] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[156] one which recognizes ligands from exogenous microbes and a variety of endogenous substrates. This family of genes has been studied most extensively in the context of autoimmune disease, but there also have been a series of studies that have analyzed genetic variants in various members of this pathway as potential prostate cancer risk modifiers.[157-161] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.

One study was based upon 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[162] These investigators genotyped 28 SNPs in a region on chromosome 4p14 that includes TLR-10, TLR-1, and TLR-6, three members of the toll-like receptor gene cluster. Two TLR-10 SNPs and four TLR-1 SNPs were associated with significant reductions in prostate cancer risk, ranging from 29% to 38% for the homozygous variant genotype. A more detailed analysis demonstrated these six SNPs were not independent in their effect, but rather represented a single strong association with reduced risk (OR, 0.55; 95% CI, 0.330.90). There were no significant differences in this association when covariates such as Gleason score, history of benign prostatic hypertrophy, use of nonsteroidal anti-inflammatory drugs, and body mass index were taken into account. This is the largest study undertaken to date and included the most comprehensive panel of SNPs evaluated in the 4p14 region. While these observations provide a basis for further investigation of the toll-like receptor genes in prostate cancer etiology, inconsistencies with the prior studies and lack of information regarding what the biological basis of these associations might be warrant caution in interpreting the findings.

SNPs in genes involved in the steroid hormone pathway have previously been studied in sporadic and familial prostate cancer using a sample of individuals with primarily Caucasian ancestry.[163] Another study evaluated 116 tagging SNPs located in 12 genes in the steroid hormone pathway for risk of prostate cancer in 886 cases and 1,566 controls encompassing non-Hispanic white men, Hispanic white men, and African American men.[164] The genes included CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1. Several SNPs in CYP19 were associated with prostate cancer risk in all three populations. Analysis of SNP-SNP interactions involving SNPs in multiple genes revealed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic whites (P = .001). In non-Hispanic whites, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < .001). In African Americans, SNPs within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1 showed a significant interaction (P = .014). In non-Hispanic whites, a cumulative risk of prostate cancer was observed for men carrying risk alleles at three SNPs in HSD3B2 and CYP19 (OR, 2.20; 95% CI, 1.443.38; P = .0003). In Hispanic whites, a cumulative risk of prostate cancer was observed for men carrying risk alleles at two SNPs in CYP19 and CYP24A1 (OR, 4.29; 95% CI, 2.118.72; P = .00006). While this study did not evaluate all potentially important SNPs in genes in the steroid hormone pathway, it demonstrates how studies can be performed to evaluate multigenic effects in multiple populations to assess the contribution to prostate cancer risk.

A meta-analysis of the relationship between eight polymorphisms in six genes (MTHFR, MTR, MTHFD1, SLC19A1, SHMT1, and FOLH1) from the folate pathway was conducted by pooling data from eight case-control studies, four GWAS, and a nested case-control study named Prostate Testing for Cancer and Treatment in the United Kingdom. Numbers of tested subjects varied among these polymorphisms, with up to 10,743 cases and 35,821 controls analyzed. The report concluded that known common folate-pathway SNPs do not have significant effects on prostate cancer susceptibility in white men.[165]

Four SNPs in the p53 pathway (three in genes regulating p53 function including MDM2, MDM4, and HAUSP and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based prostate cancer cohort of men with Caucasian ethnicity (N = 4,073).[166] However, a subsequent meta-analysis of case-control studies that focused on MDM2 (T309G) and prostate cancer risk revealed no association.[167] Therefore, the biologic basis of the various associations identified requires further study.

Table 3 summarizes additional case-control studies that have assessed genes that are potentially associated with prostate cancer susceptibility.

Case-control studies assessed site-specific prostate cancer susceptibility in the following genes: EMSY, KLF6, AMACR, NBS1, CHEK2, AR, SRD5A2, ER-beta, E-cadherin, and the toll-like receptor genes. These studies have been complicated by the later-onset nature of the disease and the high background rate of prostate cancer in the general population. In addition, there is likely to be real, extensive locus heterogeneity for hereditary prostate cancer, as suggested by both segregation and linkage studies. In this respect, hereditary prostate cancer resembles a number of the other major adult-onset hereditary cancer syndromes, in which more than one gene can produce the same or very similar clinical phenotype (e.g., hereditary breast/ovarian cancer, Lynch syndrome, hereditary melanoma, and hereditary renal cancer). The clinical validity and utility of genetic testing for any of these genes based solely on evidence for hereditary prostate cancer susceptibility has not been established.

Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[178] This approach is most effective when applied to individuals whose admixture was recent and consists of two populations who had previously been separated for thousands of years. The genomes of such individuals are a mosaic, comprised of large blocks from each ancestral locale. The technique takes advantage of a difference in disease incidence in one ancestral group compared with another. Genetic risk loci are presumed to reside in regions enriched for the ancestral group with higher incidence. Successful mapping depends on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[179,180]

Admixture mapping is a particularly attractive method for identifying genetic loci associated with increased prostate cancer risk among African Americans. African American men are at higher risk of developing prostate cancer than are men of European ancestry, and the genomes of African American men are mosaics of regions from Africa and regions from Europe. It is therefore hypothesized that inherited variants accounting for the difference in incidence between the two groups must reside in regions enriched for African ancestry. In prostate cancer admixture studies, genetic markers for ancestry were genotyped genome-wide in African American cases and controls in a search for areas enriched for African ancestry in the men with prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:

An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry.[182] As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS.[179] (Refer to the GWAS section of this summary for more information.)

Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[183] including prostate cancer. This approach can be contrasted with linkage analysis, which searches for genetic risk variants co-segregating within families that have a high prevalence of disease. Linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial). GWAS, on the other hand, are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given ancestral population (e.g., men of European ancestry). GWAS survey all common inherited variants across the genome, searching for alleles that are associated with incidence of a given disease or phenotype.[184,185] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to scan the genome without having to test all tens of millions of known SNPs. GWAS can test approximately 1 million to 5 million SNPs and ascertain almost all common inherited variants in the genome.

In a GWAS, allele frequency is compared for each SNP between cases and controls. Promising signalsin which allele frequencies deviate significantly in case compared to control populationsare validated in replication cohorts. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because 1 million SNPs are typically evaluated in a GWAS, false-positive findings are expected to occur frequently when standard statistical thresholds are used. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P < 1 10-7.[186-188]

To date, approximately 100 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (see Table 4).[189] These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. However, the findings should be qualified with a few important considerations:

The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[192]

In 2006, two genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. Using a technique called admixture mapping, a 3.8 megabase (Mb) region emerged as significantly involved with risk in African American men.[69] In another study, linkage analysis of 323 Icelandic prostate cancer cases also revealed an 8q24 risk locus.[68] Detailed genotyping of this region and an association study for prostate cancer risk in three case-control populations in Sweden, Iceland, and the United States revealed specific 8q24 risk markers: a SNP, rs1447295, and a microsatellite polymorphism, allele-8 at marker DG8S737.[68] The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in an African American case-control population, and the population attributable risk was 16%.[68] These results were confirmed in several large, independent cohorts.[70-73,80-83,193] Subsequent GWAS independently converged on another risk variant at 8q24, rs6983267.[73-75] Fine mapping, genotyping a large number of variants densely packed within a region of interest in many cases and controls, was performed across 8q24 targeting the variants most significantly associated with prostate cancer risk. Across multiple ethnic populations, three distinct 8q24 risk loci were described: region 1 (containing rs1447295) at 128.54128.62 Mb, region 2 at 128.14128.28 Mb, and region 3 (containing rs6983267) at 128.47128.54 Mb.[75] Variants within each of these three regions independently confer disease risk with ORs ranging from 1.11 to 1.66. In 2009, two separate GWAS uncovered two additional risk regions at 8q24. In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[86,87]

Since the discovery of prostate cancer risk loci at 8q24, other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. The most convincing associations reported to date for men of European ancestry are included in Table 4. The association between risk and allele status for each variant listed in Table 4 reached genome-wide statistical significance in more than one independent cohort.

Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNP frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[206] Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are included in Table 5. The association between risk and allele status for each variant listed in Table 5 reached genome-wide statistical significance in more than one independent cohort.

The African American population is of particular interest because American men with African ancestry are at higher risk of prostate cancer than any other group. In addition, inherited variation at the 8q24 risk locus appears to contribute to differences in African American and European American incidence of disease.[69] A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls.[208] On average, risk allele frequencies were 0.05 greater in African Americans than in European Americans. Of the 37 known risk SNPs analyzed, 18 replicated in the African American population were significantly associated with prostate cancer at P .05 (the study was underpowered to properly assess nine of the remaining 19 SNPs). For seven risk regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), fine mapping identified SNPs in the African American population more strongly associated with risk than the index SNPs reported in the original European-based GWAS. Fine mapping of the 8q24 region revealed four SNPs associated with disease that are substantially more common in African Americans. The SNP most strongly correlated with disease among African Americans (rs6987409) is not strongly correlated with a European risk allele and may account for a portion of increased risk in the African American population. In all, the risk SNPs identified in this study are estimated to represent 11% of total inherited risk.

Some of the risk variants identified in Table 5 have also been found to confer risk in men of European ancestry. These include rs16901979, rs6983267, and rs1447295 at 8q24 in African Americans and rs13254738 in Japanese populations. Additionally, the Japanese rs4430796 at 17q12 and rs2660753 at 3p12 have also been observed in men of European ancestry. However, the vast majority of the variants identified in these studies reveal novel variants that are unique to that specific ethnic population. These results confirm the importance of evaluating SNP associations in different ethnic populations. Considerable effort is still needed to fully annotate genetic risk in these and other populations.

Because the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. In an attempt to determine the potential clinical value of risk SNP genotype, cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region.[78] Known risk SNPs from 8q24, 17q12, and 17q24.3 were analyzed (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five risk alleles had an increasing likelihood of having prostate cancer compared with men carrying none of the alleles (P = 6.75 10-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these alleles had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.936.80; P = 1.20 10-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk of prostate cancer (OR, 9.46; 95% CI, 3.6224.72; P = 1.29 10-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.

A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases and 1,157 controls) and the Cancer of the Prostate in Sweden (CAPS) study (2,899 cases and 1,722 controls). The highest risk of prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.646.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.835.33).[214]

However, the proportion of men carrying large numbers of the risk alleles was low. While ORs were impressively high for this subset, they do not reflect the utility of genotyping the overall population. Receiver operating characteristic curves were constructed in these studies to measure the sensitivity and specificity of certain risk profiles. The area under the curve (AUC) was 0.61 when age, geographic region, and family history were used to assess risk. When genotype of the five risk SNPs at chromosomes 8 and 17 were introduced, a very modest AUC improvement to 0.63 was detected.[78] The addition of more recently discovered SNPs to the model has not appreciably improved these results.[215] While genotype may inform risk status for the small minority of men carrying multiple risk alleles, testing of the known panel of prostate cancer SNPs is currently of questionable clinical utility.[216]

Another study incorporated 10,501 prostate cancer cases and 10,831 controls from multiple cohorts (including PLCO) and genotyped each individual for 25 prostate cancer risk SNPs. Age and family history data were available for all subjects. Genotype data helped discriminate those who developed prostate cancer from those who did not. However, similar to the series above, discriminative ability was modest and only compelling at the extremes of risk allele distribution in a relatively small subset population; younger subjects (men aged 50 to 59 years) with a family history of disease who were in 90th percentile for risk allele status had an absolute 10-year risk of 6.7% compared with an absolute 10-year risk of 1.6% in men in the 10th percentile for risk allele status.[217]

In another study, 49 risk SNPs were genotyped in 2,696 Swedish men, and a polygenic risk score was calculated. On the basis of their genetic risk scores, 172 men aged 50 to 69 years with PSA levels of 1 to 3 ng/mL underwent biopsy. Prostate cancer was diagnosed in 27% of these individuals, and 6% had Gleason 7 or higher disease.[218] The utility of this strategy for identifying who should undergo prostate biopsy is yet to be determined.

In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS.[216] Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNPs have poor discriminative ability to identify individuals at risk of developing the disease. Similarly, the authors of another study estimated that the contribution of GWAS polymorphisms in determining the risk of developing prostate cancer will be modest, even as meta-analyses or larger studies uncover additional common risk alleles (alleles carried by >1%5% of individuals within the population).[219]

GWAS findings to date account for only a fraction of heritable risk of disease. Research is ongoing to uncover the remaining portion of genetic risk. This includes the discovery of rarer alleles with higher ORs for risk. For example, a consortium led by deCODE genetics in Iceland performed whole-genome sequencing of 2,500 Icelanders and identified approximately 32.5 million variants, including millions of rare variants (carried by <1% of the population). These variants were analyzed in 5,141 prostate cancer cases and 54,444 controls (genotypes were imputed in cases in which they had not been genotyped in previous analyses). In addition to previously reported risk alleles at 8q24 and 17q12, significant associations with prostate cancer were observed for two rare 8q24 SNPsthe minor allele (the G allele) of rs183373024 (OR, 2.69; P = 1.5 1023) and the minor allele (the A allele) of rs188140481 (OR, 2.88; P = 1.5 1022).[220] These results were validated in independent cohorts of European cases and controls. The frequencies of the risk alleles of these two variants in controls ranged from 0.1% to 1.1% and were lowest in southern Europe and highest in northern Europe. These data, in which risk alleles had high ORs compared with previous GWAS, demonstrate that the bulk of inherited risk may reside in rare alleles.

In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful.

Notably, almost all reported prostate cancer risk alleles reside in nonprotein coding regions of the genome, and the underlying biological mechanism of disease susceptibility remains unclear. Hypotheses explaining the mechanism of inherited risk include the following:

The 8q24 risk locus, which contains multiple prostate cancer risk alleles and risk alleles for other cancers, has been the focus of intense study. c-MYC, a known oncogene, is the closest known gene to the 8q24 risk regions, although it is located hundreds of kb away. Given this significant distance, SNPs within c-MYC are not in linkage disequilibrium with the 8q24 prostate cancer risk variants. One study examined whether 8q24 prostate cancer risk SNPs are in fact located in areas of previously unannotated transcription, and no transcriptional activity was uncovered at the risk loci.[222] Attention turned to the idea of distal gene regulation. Interrogation of the epigenetic landscape at the 8q24 risk loci revealed that the risk variants are located in areas that bear the marks of genetic enhancers, elements that influence gene activity from a distance.[223-225] To identify a prostate cancer risk gene, germline DNA from 280 men undergoing prostatectomy for prostate cancer was genotyped for all known 8q24 risk SNPs. Genotypes were tested for association with the normal prostate and prostate tumor RNA expression levels of genes located within one Mb of the risk SNPs. No association was detected between expression of any of the genes, including c-MYC, and risk allele status in either normal epithelium or tumor tissue. Another study, using normal prostate tissue from 59 patients, detected an association between an 8q24 risk allele and the gene PVT1, downstream from c-MYC.[226] Nonetheless, c-MYC, with its substantial involvement in many cancers, remains a prime candidate. A series of experiments in prostate cancer cell lines demonstrated that chromatin is configured in such a way that the 8q24 risk variants lie in close proximity to c-MYC, even though they are quite distant in linear space. These data implicate c-MYC despite the absence of expression data.[224,226] Further work at 8q24 and similar analyses at other prostate cancer risk loci are ongoing.

Additional insights are emerging regarding the potential interaction between SNPs identified from GWAS and prostate cancer susceptibility gene regulation. One study found that a SNP at 6q22 lies within a binding region for HOXB13. Through multiple functional approaches, the T allele of this SNP (rs339331) was found to enhance binding of HOXB13, leading to allele-specific upregulation of RFX6, which correlates with prostate cancer progression and severity.[227] Thus, this study supports the hypothesis that risk alleles identified from GWAS may play a role in regulating or modifying gene expression and therefore impact prostate cancer risk.

A 2012 study used a novel approach to identify polymorphisms associated with risk.[228] On the basis of the well-established principle that the AR plays a prominent role in prostate tumorigenesis, the investigators targeted SNPs that reside at sites where the AR binds to DNA. They leveraged data from previous studies that mapped thousands of AR binding sites genome-wide in prostate cancer cell lines to select SNPs to genotype in the Johns Hopkins Hospital cohort of 1,964 cases and 3,172 controls and the Cancer Genetic Markers of Susceptibility cohort of 1,172 cases and 1,157 controls. This modified GWAS revealed a SNP (rs4919743) located at the KRT8 locus at 12q13.13a locus previously implicated in cancer developmentassociated with prostate cancer risk, with an OR of 1.22 (95% CI, 1.131.32). The study is notable for its use of a reasonable hypothesis and prior data to guide a genome-wide search for risk variants.

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project.[229] Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.

Prostate cancer is clinically heterogeneous. Many cases are indolent and are successfully managed with observation alone. Other cases are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed, as sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers since they are present, easily detectable, and static throughout life. Several studies have interrogated inherited variants that may distinguish indolent and aggressive prostate cancer. Several of these studies identified polymorphisms associated with aggressiveness, after adjusting for commonly used clinical variables, and are reviewed in the Table 6.

Findings to date regarding inherited risk of aggressive disease are considered preliminary. Further work is needed to validate findings and assess prospectively.

Like studies of the genetics of prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes. Next, as GWAS revealed prostate cancer risk SNPs, several research teams sought to determine whether certain risk SNPs were also associated with aggressiveness (see table below). There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer. While GWAS designed explicitly for disease aggressiveness have been initiated, most genome-wide analyses to date have relied on datasets previously generated to evaluate prostate cancer risk. The cases from these case-control cohorts were divided into aggressive and nonaggressive subgroups then compared with each other and/or with the control (nonprostate cancer) subjects. Several associations between germline markers and prostate cancer aggressiveness have been reported. However, there remains no accepted set of germline markers that clearly provides prognostic information beyond that provided by more traditional variables at the time of diagnosis.

In independent retrospective series (see Table 6) the prostate cancer risk allele at rs2735839 (G) was associated with less aggressive disease. This risk allele has also been associated with higher PSA levels.[198,238] A hypothesis explaining the association between the nonrisk allele (A) and more aggressive disease is that those carrying the A allele generally have lower PSA levels and are sent for prostate biopsy less often. They subsequently may be diagnosed later in the natural history of the disease, resulting in poorer outcomes.

To definitively identify the inherited variants associated with prostate cancer aggressiveness, GWAS focusing on prostate cancer subjects with poor disease-related outcomes are needed. Notably, in a genome-wide analysis in which two of the largest international prostate cancer genotyped cohorts were combined for analysis (24,023 prostate cancer cases, including 3,513 disease-specific deaths), no SNP was associated with prostate cancerspecific survival.[239] The authors concluded that any SNP associated with prostate cancer outcome must be fairly rare in the general population (minor allele frequency below 1%). As more data regarding rarer variants are generated and validated, the value of inherited variants for therapeutic decision making may be determined.

While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported that prostate cancer risk is elevated in men with mutations in BRCA1, BRCA2, and on a smaller scale, in mismatch repair (MMR) genes. Since clinical genetic testing is available for these genes, information about risk of prostate cancer based on alterations in these genes is included in this section. In addition, mutations in HOXB13 were reported to account for a proportion of hereditary prostate cancer. Although clinical testing is not yet available for HOXB13 alterations, it is expected that this gene will have clinical relevance in the future and therefore it is also included in this section. The genetic alterations described in this section require further study and are not to be used in routine clinical practice at this time.

Studies of male BRCA1 [1] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2] Prostate cancer in particular has been observed at higher rates in male BRCA2 mutations carriers than in the general population.[3]

The risk of prostate cancer in BRCA mutation carriers has been studied in various settings.

In an effort to clarify the relationship between BRCA mutations and prostate cancer risk, findings from several case series are summarized in Table 7.

Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline mutations in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[6] In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.

Several studies in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi Jewish (AJ) men with prostate cancer.[7-9] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.71.1) for the 185delAG mutation, 0.3% (95% confidence interval [CI], 0.20.4) for the 5382insC mutation, and 1.3% (95% CI, 1.01.5) for the BRCA2 6174delT mutation.[10-13] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks (RRs) were commonly greater than 1, but only a few have been statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder mutations.

In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia, area who carried one of the BRCA Ashkenazi founder mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 430) among carriers and 3.8% among noncarriers (95% CI, 3.34.4).[13] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by age 70 years; 95% CI, 628). The risk of prostate cancer in male mutation carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

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