Monthly Archives: July 2017

Human genetics, study of the inheritance of characteristics by children from parents. Inheritance in humans does not differ in any fundamental way from that in other organisms.

The study of human heredity occupies a central position in genetics. Much of this interest stems from a basic desire to know who humans are and why they are as they are. At a more practical level, an understanding of human heredity is of critical importance in the prediction, diagnosis, and treatment of diseases that have a genetic component. The quest to determine the genetic basis of human health has given rise to the field of medical genetics. In general, medicine has given focus and purpose to human genetics, so the terms medical genetics and human genetics are often considered synonymous.

A new era in cytogenetics, the field of investigation concerned with studies of the chromosomes, began in 1956 with the discovery by Jo Hin Tjio and Albert Levan that human somatic cells contain 23 pairs of chromosomes. Since that time the field has advanced with amazing rapidity and has demonstrated that human chromosome aberrations rank as major causes of fetal death and of tragic human diseases, many of which are accompanied by mental retardation. Since the chromosomes can be delineated only during mitosis, it is necessary to examine material in which there are many dividing cells. This can usually be accomplished by culturing cells from the blood or skin, since only the bone marrow cells (not readily sampled except during serious bone marrow disease such as leukemia) have sufficient mitoses in the absence of artificial culture. After growth, the cells are fixed on slides and then stained with a variety of DNA-specific stains that permit the delineation and identification of the chromosomes. The Denver system of chromosome classification, established in 1959, identified the chromosomes by their length and the position of the centromeres. Since then the method has been improved by the use of special staining techniques that impart unique light and dark bands to each chromosome. These bands permit the identification of chromosomal regions that are duplicated, missing, or transposed to other chromosomes.

Micrographs showing the karyotypes (i.e., the physical appearance of the chromosome) of a male and a female have been produced. In a typical micrograph the 46 human chromosomes (the diploid number) are arranged in homologous pairs, each consisting of one maternally derived and one paternally derived member. The chromosomes are all numbered except for the X and the Y chromosomes, which are the sex chromosomes. In humans, as in all mammals, the normal female has two X chromosomes and the normal male has one X chromosome and one Y chromosome. The female is thus the homogametic sex, as all her gametes normally have one X chromosome. The male is heterogametic, as he produces two types of gametesone type containing an X chromosome and the other containing a Y chromosome. There is good evidence that the Y chromosome in humans, unlike that in Drosophila, is necessary (but not sufficient) for maleness.

Read More on This Topic

genetics: Human genetics

Some geneticists specialize in the hereditary processes of human genetics. Most of the emphasis is on understanding and treating genetic disease and genetically influenced ill health, areas collectively known as medical genetics. One broad area of activity is laboratory research dealing with the mechanisms of human gene function and malfunction and investigating pharmaceutical and other types...

A human individual arises through the union of two cells, an egg from the mother and a sperm from the father. Human egg cells are barely visible to the naked eye. They are shed, usually one at a time, from the ovary into the oviducts (fallopian tubes), through which they pass into the uterus. Fertilization, the penetration of an egg by a sperm, occurs in the oviducts. This is the main event of sexual reproduction and determines the genetic constitution of the new individual.

Test Your Knowledge

Science Quiz

Human sex determination is a genetic process that depends basically on the presence of the Y chromosome in the fertilized egg. This chromosome stimulates a change in the undifferentiated gonad into that of the male (a testicle). The gonadal action of the Y chromosome is mediated by a gene located near the centromere; this gene codes for the production of a cell surface molecule called the H-Y antigen. Further development of the anatomic structures, both internal and external, that are associated with maleness is controlled by hormones produced by the testicle. The sex of an individual can be thought of in three different contexts: chromosomal sex, gonadal sex, and anatomic sex. Discrepancies between these, especially the latter two, result in the development of individuals with ambiguous sex, often called hermaphrodites. The phenomenon of homosexuality is of uncertain cause and is unrelated to the above sex-determining factors. It is of interest that in the absence of a male gonad (testicle) the internal and external sex anatomy is always female, even in the absence of a female ovary. A female without ovaries will, of course, be infertile and will not experience any of the female developmental changes normally associated with puberty. Such a female will often have Turners syndrome.

If X-containing and Y-containing sperm are produced in equal numbers, then according to simple chance one would expect the sex ratio at conception (fertilization) to be half boys and half girls, or 1 : 1. Direct observation of sex ratios among newly fertilized human eggs is not yet feasible, and sex-ratio data are usually collected at the time of birth. In almost all human populations of newborns, there is a slight excess of males; about 106 boys are born for every100 girls. Throughout life, however, there is a slightly greater mortality of males; this slowly alters the sex ratio until, beyond the age of about 50 years, there is an excess of females. Studies indicate that male embryos suffer a relatively greater degree of prenatal mortality, so the sex ratio at conception might be expected to favour males even more than the 106 : 100 ratio observed at birth would suggest. Firm explanations for the apparent excess of male conceptions have not been established; it is possible that Y-containing sperm survive better within the female reproductive tract, or they may be a little more successful in reaching the egg in order to fertilize it. In any case, the sex differences are small, the statistical expectation for a boy (or girl) at any single birth still being close to one out of two.

Britannica Lists & Quizzes

Geography List

Health & Medicine Quiz

Literature & Language List

During gestationthe period of nine months between fertilization and the birth of the infanta remarkable series of developmental changes occur. Through the process of mitosis, the total number of cells changes from 1 (the fertilized egg) to about 2 1011. In addition, these cells differentiate into hundreds of different types with specific functions (liver cells, nerve cells, muscle cells, etc.). A multitude of regulatory processes, both genetically and environmentally controlled, accomplish this differentiation. Elucidation of the exquisite timing of these processes remains one of the great challenges of human biology.

Immunity is the ability of an individual to recognize the self molecules that make up ones own body and to distinguish them from such nonself molecules as those found in infectious microorganisms and toxins. This process has a prominent genetic component. Knowledge of the genetic and molecular basis of the mammalian immune system has increased in parallel with the explosive advances made in somatic cell and molecular genetics.

There are two major components of the immune system, both originating from the same precursor stem cells. The bursa component provides B lymphocytes, a class of white blood cells that, when appropriately stimulated, differentiate into plasma cells. These latter cells produce circulating soluble proteins called antibodies or immunoglobulins. Antibodies are produced in response to substances called antigens, most of which are foreign proteins or polysaccharides. An antibody molecule can recognize a specific antigen, combine with it, and initiate its destruction. This so-called humoral immunity is accomplished through a complicated series of interactions with other molecules and cells; some of these interactions are mediated by another group of lymphocytes, the T lymphocytes, which are derived from the thymus gland. Once a B lymphocyte has been exposed to a specific antigen, it remembers the contact so that future exposure will cause an accelerated and magnified immune reaction. This is a manifestation of what has been called immunological memory.

The thymus component of the immune system centres on the thymus-derived T lymphocytes. In addition to regulating the B cells in producing humoral immunity, the T cells also directly attack cells that display foreign antigens. This process, called cellular immunity, is of great importance in protecting the body against a variety of viruses as well as cancer cells. Cellular immunity is also the chief cause of the rejection of organ transplants. The T lymphocytes provide a complex network consisting of a series of helper cells (which are antigen-specific), amplifier cells, suppressor cells, and cytotoxic (killer) cells, all of which are important in immune regulation.

One of the central problems in understanding the genetics of the immune system has been in explaining the genetic regulation of antibody production. Immunobiologists have demonstrated that the system can produce well over one million specific antibodies, each corresponding to a particular antigen. It would be difficult to envisage that each antibody is encoded by a separate gene; such an arrangement would require a disproportionate share of the entire human genome. Recombinant DNA analysis has illuminated the mechanisms by which a limited number of immunoglobulin genes can encode this vast number of antibodies.

Each antibody molecule consists of several different polypeptide chainsthe light chains (L) and the longer heavy chains (H). The latter determine to which of five different classes (IgM, IgG, IgA, IgD, or IgE) an immunoglobulin belongs. Both the L and H chains are unique among proteins in that they contain constant and variable parts. The constant parts have relatively identical amino acid sequences in any given antibody. The variable parts, on the other hand, have different amino acid sequences in each antibody molecule. It is the variable parts, then, that determine the specificity of the antibody.

Recombinant DNA studies of immunoglobulin genes in mice have revealed that the light-chain genes are encoded in four separate parts in germ-line DNA: a leader segment (L), a variable segment (V), a joining segment (J), and a constant segment (C). These segments are widely separated in the DNA of an embryonic cell, but in a mature B lymphocyte they are found in relative proximity (albeit separated by introns). The mouse has more than 200 light-chain variable region genes, only one of which will be incorporated into the proximal sequence that codes for the antibody production in a given B lymphocyte. Antibody diversity is greatly enhanced by this system, as the V and J segments rearrange and assort randomly in each B-lymphocyte precursor cell. The mechanisms by which this DNA rearrangement takes place are not clear, but transposons are undoubtedly involved. Similar combinatorial processes take place in the genes that code for the heavy chains; furthermore, both the light-chain and heavy-chain genes can undergo somatic mutations to create new antibody-coding sequences. The net effect of these combinatorial and mutational processes enables the coding of millions of specific antibody molecules from a limited number of genes. It should be stressed, however, that each B lymphocyte can produce only one antibody. It is the B lymphocyte population as a whole that produces the tremendous variety of antibodies in humans and other mammals.

Plasma cell tumours (myelomas) have made it possible to study individual antibodies, since these tumours, which are descendants of a single plasma cell, produce one antibody in abundance. Another method of obtaining large amounts of a specific antibody is by fusing a B lymphocyte with a rapidly growing cancer cell. The resultant hybrid cell, known as a hybridoma, multiplies rapidly in culture. Since the antibodies obtained from hybridomas are produced by clones derived from a single lymphocyte, they are called monoclonal antibodies.

As has been stated, cellular immunity is mediated by T lymphocytes that can recognize infected body cells, cancer cells, and the cells of a foreign transplant. The control of cellular immune reactions is provided by a linked group of genes, known as the major histocompatibility complex (MHC). These genes code for the major histocompatibility antigens, which are found on the surface of almost all nucleated somatic cells. The major histocompatibility antigens were first discovered on the leukocytes (white blood cells) and are therefore usually referred to as the HLA (human leukocyte group A) antigens.

The advent of the transplantation of human organs in the 1950s made the question of tissue compatibility between donor and recipient of vital importance, and it was in this context that the HLA antigens and the MHC were elucidated. Investigators found that the MHC resides on the short arm of chromosome 6, on four closely associated sites designated HLA-A, HLA-B, HLA-C, and HLA-D. Each locus is highly polymorphic; i.e., each is represented by a great many alleles within the human gene pool. These alleles, like those of the ABO blood group system, are expressed in codominant fashion. Because of the large number of alleles at each HLA locus, there is an extremely low probability of any two individuals (other than siblings) having identical HLA genotypes. (Since a person inherits one chromosome 6 from each parent, siblings have a 25 percent probability of having received the same paternal and maternal chromosomes 6 and thus of being HLA matched.)

Although HLA antigens are largely responsible for the rejection of organ transplants, it is obvious that the MHC did not evolve to prevent the transfer of organs from one person to another. Indeed, information obtained from the histocompatibility complex in the mouse (which is very similar in its genetic organization to that of the human) suggests that a primary function of the HLA antigens is to regulate the number of specific cytotoxic T killer cells, which have the ability to destroy virus-infected cells and cancer cells.

More is known about the genetics of the blood than about any other human tissue. One reason for this is that blood samples can be easily secured and subjected to biochemical analysis without harm or major discomfort to the person being tested. Perhaps a more cogent reason is that many chemical properties of human blood display relatively simple patterns of inheritance.

Certain chemical substances within the red blood cells (such as the ABO and MN substances noted above) may serve as antigens. When cells that contain specific antigens are introduced into the body of an experimental animal such as a rabbit, the animal responds by producing antibodies in its own blood.

In addition to the ABO and MN systems, geneticists have identified about 14 blood-type gene systems associated with other chromosomal locations. The best known of these is the Rh system. The Rh antigens are of particular importance in human medicine. Curiously, however, their existence was discovered in monkeys. When blood from the rhesus monkey (hence the designation Rh) is injected into rabbits, the rabbits produce so-called Rh antibodies that will agglutinate not only the red blood cells of the monkey but the cells of a large proportion of human beings as well. Some people (Rh-negative individuals), however, lack the Rh antigen; the proportion of such persons varies from one human population to another. Akin to data concerning the ABO system, the evidence for Rh genes indicates that only a single chromosome locus (called r) is involved and is located on chromosome 1. At least 35 Rh alleles are known for the r location; basically the Rh-negative condition is recessive.

A medical problem may arise when a woman who is Rh-negative carries a fetus that is Rh-positive. The first such child may have no difficulty, but later similar pregnancies may produce severely anemic newborn infants. Exposure to the red blood cells of the first Rh-positive fetus appears to immunize the Rh-negative mother, that is, she develops antibodies that may produce permanent (sometimes fatal) brain damage in any subsequent Rh-positive fetus. Damage arises from the scarcity of oxygen reaching the fetal brain because of the severe destruction of red blood cells. Measures are available for avoiding the severe effects of Rh incompatibility by transfusions to the fetus within the uterus; however, genetic counselling before conception is helpful so that the mother can receive Rh immunoglobulin immediately after her first and any subsequent pregnancies involving an Rh-positive fetus. This immunoglobulin effectively destroys the fetal red blood cells before the mothers immune system is stimulated. The mother thus avoids becoming actively immunized against the Rh antigen and will not produce antibodies that could attack the red blood cells of a future Rh-positive fetus.

Human serum, the fluid portion of the blood that remains after clotting, contains various proteins that have been shown to be under genetic control. Study of genetic influences has flourished since the development of precise methods for separating and identifying serum proteins. These move at different rates under the impetus of an electrical field (electrophoresis), as do proteins from many other sources (e.g., muscle or nerve). Since the composition of a protein is specified by the structure of its corresponding gene, biochemical studies based on electrophoresis permit direct study of tissue substances that are only a metabolic step or two away from the genes themselves.

Electrophoretic studies have revealed that at least one-third of the human serum proteins occur in variant forms. Many of the serum proteins are polymorphic, occurring as two or more variants with a frequency of not less than 1 percent each in a population. Patterns of polymorphic serum protein variants have been used to determine whether twins are identical (as in assessing compatibility for organ transplants) or whether two individuals are related (as in resolving paternity suits). Whether the different forms have a selective advantage is not generally known.

Much attention in the genetics of substances in the blood has been centred on serum proteins called haptoglobins, transferrins (which transport iron), and gamma globulins (a number of which are known to immunize against infectious diseases). Haptoglobins appear to relate to two common alleles at a single chromosome locus; the mode of inheritance of the other two seems more complicated, about 18 kinds of transferrins having been described. Like blood-cell antigen genes, serum-protein genes are distributed worldwide in the human population in a way that permits their use in tracing the origin and migration of different groups of people.

Hundreds of variants of hemoglobin have been identified by electrophoresis, but relatively few are frequent enough to be called polymorphisms. Of the polymorphisms, the alleles for sickle-cell and thalassemia hemoglobins produce serious disease in homozygotes, whereas others (hemoglobins C, D, and E) do not. The sickle-cell polymorphism confers a selective advantage on the heterozygote living in a malarial environment; the thalassemia polymorphism provides a similar advantage.

As stated earlier in this article, gene expression occurs only after modification by the environment. A good example is the recessively inherited disease called galactosemia, in which the enzyme necessary for the metabolism of galactosea component of milk sugaris defective. The sole source of galactose in the infants diet is milk, which in this instance is toxic. The treatment of this most serious disease in the neonate is to remove all natural forms of milk from the diet (environmental manipulation) and to substitute a synthetic milk lacking galactose. The infant will then develop normally but will never be able to tolerate foods containing lactose. If milk was not a major part of the infants diet, however, the mutant gene would never be able to express itself, and galactosemia would be unknown.

Another way of saying this is that no trait can exist or become actual without an environmental contribution. Thus, the old question of which is more important, heredity or environment, is without meaning. Both nature (heredity) and nurture (environment) are always important for every human attribute.

But this is not to say that the separate contributions of heredity and environment are equivalent for each characteristic. Dark pigmentation of the iris of the eye, for example, is under hereditary control in that one or more genes specify the synthesis and deposition in the iris of the pigment (melanin). This is one characteristic that is relatively independent of such environmental factors as diet or climate; thus, individual differences in eye colour tend to be largely attributable to hereditary factors rather than to ordinary environmental change.

On the other hand, it is unwarranted to assume that other traits (such as height, weight, or intelligence) are as little affected by environment as is eye colour. It is very easy to gather information that tall parents tend, on the average, to have tall children (and that short parents tend to produce short children), properly indicating a hereditary contribution to height. Nevertheless, it is equally manifest that growth can be stunted in the environmental absence of adequate nutrition. The dilemma arises that only the combined, final result of this nature-nurture interaction can be directly observed. There is no accurate way (in the case of a single individual) to gauge the separate contributions of heredity and environment to such a characteristic as height. An inferential way out of this dilemma is provided by studies of twins.

Usually a fertile human female produces a single egg about once a month. Should fertilization occur (a zygote is formed), growth of the individual child normally proceeds after the fertilized egg has become implanted in the wall of the uterus (womb). In the unusual circumstance that two unfertilized eggs are simultaneously released by the ovaries, each egg may be fertilized by a different sperm cell at about the same time, become implanted, and grow, to result in the birth of twins.

Twins formed from separate eggs and different sperm cells can be of the same or of either sex. No matter what their sex, they are designated as fraternal twins. This terminology is used to emphasize that fraternal twins are genetically no more alike than are siblings (brothers or sisters) born years apart. Basically they differ from ordinary siblings only in having grown side by side in the womb and in having been born at approximately the same time.

In a major nonfraternal type of twinning, only one egg is fertilized, but during the cleavage of this single zygote into two cells, the resulting pair somehow become separated. Each of the two cells may implant in the uterus separately and grow into a complete, whole individual. In laboratory studies with the zygotes of many animal species, it has been found that in the two-cell stage (and later) a portion of the embryo, if separated under the microscope by the experimenter, may develop into a perfect, whole individual. Such splitting occurs spontaneously at the four-cell stage in some organisms (e.g., the armadillo) and has been accomplished experimentally with the embryos of salamanders, among others.

The net result of splitting at an early embryonic stage may be to produce so-called identical twins. Since such twins derive from the same fertilized egg, the hereditary material from which they originate is absolutely identical in every way, down to the last gene locus. While developmental and genetic differences between one identical twin and another still may arise through a number of processes (e.g., mutation), these twins are always found to be of the same sex. They are often breathtakingly similar in appearance, frequently down to very fine anatomic and biochemical details (although their fingerprints are differentiable).

Since the initial event in the mothers body (either splitting of a single egg or two separate fertilizations) is not observed directly, inferential means are employed for diagnosing a set of twins as fraternal or identical. The birth of fraternal twins is frequently characterized by the passage of two separate afterbirths. In many instances, identical twins are followed by only a single afterbirth, but exceptions to this phenomenon are so common that this is not a reliable method of diagnosis.

The most trustworthy method for inferring twin type is based on the determination of genetic similarity. By selecting those traits that display the least variation attributable to environmental influences (such as eye colour and blood types), it is feasible, if enough separate chromosome loci are considered, to make the diagnosis of twin type with high confidence. HLA antigens, which, as stated above, are very polymorphic, have become most useful in this regard.

By measuring the heights of a large number of ordinary siblings (brothers and sisters) and of twin pairs, it may be shown that the average difference between identical twins is less than half the difference for all other siblings. Any average differences between groups of identical twins are attributable with considerable confidence to the environment. Thus, since the sample of identical twins who were reared apart (in different homes) differed little in height from identicals who were raised together, it appears that environmental-genetic influences on that trait tended to be similar for both groups.

Yet, the data for like-sexed fraternal twins reveal a much greater average difference in height (about the same as that found between ordinary siblings reared in the same home at different ages). Apparently the fraternal twins were more dissimilar than identicals (even though reared together) because the fraternals differed more from each other in genotype. This emphasizes the great genetic similarity between identicals. Such studies can be particularly enlightening when the effects of individual genes are obscured or distorted by the influence of environmental factors on quantitative (measurable) traits (e.g., height, weight, and intelligence).

Any trait that can be objectively measured in identical and fraternal twins can be scrutinized for the particular combination of hereditary and environmental influences that impinge upon it. The effect of environment on identical twins reared apart is suggested by their relatively great average difference in body weight as compared with identical twins reared together. Weight appears to be more strongly modified by environmental variables than is height.

Study of comparable characteristics among farm animals and plants suggests that such quantitative human traits as height and weight are affected by allelic differences at a number of chromosome locationsthat they are not simply affected by genes at a single locus. Investigation of these gene systems with multiple locations (polygenic systems) is carried out largely through selective-breeding experiments among large groups of plants and lower animals. Human beings select their mates in a much freer fashion, of course, and polygenic studies among people are thus severely limited.

Intelligence is a very complex human trait, the genetics of which has been a subject of controversy for some time. Much of the controversy arises from the fact that intelligence is so difficult to define. Information has been based almost entirely on scores on standardized IQ tests constructed by psychologists; in general, such tests do not take into account cultural, environmental, and educational differences. As a result, the working definition of intelligence has been the general factor common to a large number of diverse cognitive (IQ) tests. Even roughly measured as IQ, intelligence shows a strong contribution from the environment. Fraternal twins, however, show relatively great dissimilarity in IQ, suggesting an important contribution from heredity as well. In fact, it has been estimated that, on the average, between 60 and 80 percent of the variance in IQ test scores could be genetic. It is important to note that intelligence is polygenically inherited and that it has the highest degree of assortative mating of any trait; in other words, people tend to mate with people having similar IQs. Moreover, twin studies involving psychological traits should be viewed with caution; for example, since identical twins tend to be singled out for special attention, their environment should not be considered equivalent even to that of other children raised in their own family.

Since the time of Galton, generalizations have been repeatedly made about racial differences in intelligence, with claims of genetic superiority of some races over others. These generalizations fail to recognize that races are composed of individuals, each of whom has a unique genotype made up by genes shared with other humans, and that the sources of intraracial variation are more numerous than those producing interracial differences.

For traits of a more qualitative (all-or-none) nature, the twin method can also be used in efforts to assess the degree of hereditary contribution. Such investigations are based on an examination of cases in which at least one member of the twin pair shows the trait. It was found in one study, for example, that in about 80 percent of all identical twin pairs in which one twin shows symptoms of the psychiatric disorder called schizophrenia, the other member of the pair also shows the symptoms; that is, the two are concordant for the schizophrenic trait. In the remaining 20 percent, the twins are discordant; that is, one lacks the trait. Since identical twins often have similar environments, this information by itself does not distinguish between the effects of heredity and environment. When pairs of like-sexed fraternal twins reared together are studied, however, the degree of concordance for schizophrenia is very much loweronly about 15 percent.

Schizophrenia thus clearly develops much more easily in some genotypes than in others; this indicates a strong hereditary predisposition to the development of the trait. Schizophrenia also serves as a good example of the influence of environmental factors, since concordance for the condition does not appear in 100 percent of identical twins.

Studies of concordance and discordance between identical and fraternal twins have been carried out for many other human characteristics. It has, for example, been known for many years that tuberculosis is a bacterial infection of environmental origin. Yet identical twins raised in the same home show concordance for the disease far more often than do fraternal twins. This finding seems to be explained by the high degree of genetic similarity between the identical twins. While the tuberculosis germ is not inherited, heredity does seem to make one more (or less) susceptible to this particular infection. Thus, the genes of one individual may provide the chemical basis for susceptibility to a disease, while the genes of another may fail to do so.

Indeed, there seem to be genetic differences between disease germs themselves that result in differences in their virulence. Thus, whether a genetically susceptible person actually develops a disease also depends in part on the heredity of the particular strain of bacteria or virus with which he or she must cope. Consequently, unless environmental factors such as these are adequately evaluated, the conclusions drawn from susceptibility studies can be unfortunately misleading.

The above discussion should help to make clear the limits of genetic determinism. The expression of the genotype can always be modified by the environment. It can be argued that all human illnesses have a genetic component and that the basis of all medical therapy is environmental modification. Specifically, this is the hope for the management of genetic diseases. The more that can be learned about the basic molecular and cellular dysfunctions associated with such diseases, the more amenable they will be to environmental manipulation.

Continued here:
human genetics | biology | Britannica.com

Human genetics is the study of how genes influence human traits, diseases, and behaviors, including how genetic and non-genetic factors interact. Public health genetics applies advances in human genetics and genomics to improve public health and prevent disease. Genetic counselors work as members of a health care team, providing information and support to patients dealing with birth defects or genetic disorders and those who may be at risk for inherited conditions.

The program emphasizes the study of genetic mechanisms related to the transition from normal to disease states, and studies how genes and the environment interact to affect the distribution of health and disease in human populations.

Human genetics research has helped answer fundamental questions about human nature and led to the development of effective treatments for many diseases that greatly impact human health. Faculty in the Department of Human Genetics have developed and used genetic methods to investigate the causes and treatment of hereditary and acquired human illness and to understand and explore the impact of genetics on public health, education, and disease prevention.

Originally posted here:
Human Genetics | Pitt Public Health | University of Pittsburgh

The world learned the details of the Islamic States systemic rape and slavery of women through shocking stories told to the New York Times in 2015.Our collective outrage also showed how war has changed. Rape, torture and slavery are considered beyond taboo; they are criminalized even in war. This archaic behavior is not supposed to happen in our modern world.

But thats a pretty recent development. Systemic rape used to go hand in hand with war as women, resources and landswere assimilated into the victors communities. The victorious menhad more children, more land and more power. Some researchers have argued that this is proof of the deep roots theory of war: Human males fight each other for reproductive advantage, proving that war is an evolutionary advantageous behavior.

But this theory has been hard to prove. In fact, studies of human groups and other primates have added to the evidence both for and against the controversial idea that humans were made for war, evolutionarily speaking. A January 2015study indicates that societies dont actually benefit from head-to-head action, though other forms of violence do pay off.

Harvard evolutionary biologists Luke Glowaki and Richard Wrangham studied the Nyangatom people of East Africa. The group are polygamous shepherds who raise small livestock and can have multiple wives. At times, the Nyangatom go to war with other groups. But there is a another pervasive and nearly constant form of violence in the group. Young riders make raids on nearby camps with the goal of stealing cattle. Glowaki and Wrangham asked if either or both of these types of violence was beneficial to the men who engaged in them. They measured by counting the the number of wives and kids they had.

This study is one of many that has heightened thedebate over how muchwar has had an impact on a warriors evolutionary success. At least in this society,sneaking around after dark and stealing cows may have beenmore consequential. Robert Sapolosky at the Wall Street Journal explained:

By contrast, lots of battle raidingopen-field, daytime combat with hundreds of participantsdid not serve as a predictor of elevated reproductive success, probably because such fighting carried a nontrivial chance of winding up dead. In other words, in this society, being a warrior on steroids did not predict reproductive success; being a low-down sneaky varmint of a cattle rustler did.

But researchers only discovered this by looking at the elders in the community. Stealthy animal raiding did lead to better outcomes but decades later. In Nyangatom culture, most of the stolen livestock goes to fathers and other paternal relatives rather than being kept by the young men who stole them. The male heads of families made marriage decisions for their younger relatives. So, while it this kind of violence makes a difference, the payoff is quite delayed. The researchers speculated the cattle-rustling effect would be stronger in a group where the raiders got to keep the livestock they stole and incentives were strengthened.

Other studies also point to the idea that inter-group warfare might not be beneficial, but intra-group violence is. Chimpanzee tribes, for example dont often go to war with other tribes. Instead the most common types of violence involve a group of males ganging up on one individual male. This often happens when conditions are crowded or there were increased numbers of males in the tribe. And the researchers found that chimps participation in violence happened outside of the spheres of human influence, meaning violence was not a behavior the chimpanzees learned from us.

But other evidence suggests that humans likely didnt participate in war as we know it until relatively recently. A 2013 survey of killings in 21 groups (foragers rather than shepherds) found that group warfare was rare compared to homicide. John Horgan categorized the evidence at Scientific American:

Some other points of interest: 96 percent of the killers were male. No surprise there. But some readers may be surprised that only two out of 148 killings stemmed from a fight over resources, such as a hunting ground, water hole or fruit tree. Nine episodes of lethal aggression involved husbands killing wives; three involved execution of an individual in a group by other members of the group; seven involved execution of outsiders, such as colonizers or missionaries. Most of the killings stemmed from what Fry and Soderberg categorize as miscellaneous personal disputes, involving jealousy, theft, insults and so on. The most common specific cause of deadly violenceinvolving either single or multiple perpetratorswas revenge for a previous attack.So it maybe that a proclivity for violence and an innate sense of revenge that perpetuates war, rather than war itself.

Another factor to consider is that while our common ancestors lived in groups like these thousands of years ago, almost no one does anymore. In fact, finding these undisturbed cultures is hard to do. Having more cows doesnt carry the same appeal it once did. Its unlikely stealing your neighbors TV for your uncle will fetch you a better bride. Some scientists worry that if we accept the idea that violence was a beneficial tool for our ancestors, it somehow overturns the societal progress that has moved us beyond the rape and pillage culture to something still imperfect, but largely more peaceful.

This is the biggest struggle with the deep roots theory of human violence. Just because something garnered an advantage thousands of years ago doesnt make it okay today. Harvard psychologist Steven Pinker, who has written a book on human violence, said in the Boston Globe:

romantics worry that if violence is a Darwinian adaptation, that must mean that it is good, or that its futile to work for peace, because humans have an innate thirst for blood that has to be periodically slaked. Needless to say, I think all this is profoundly wrongheaded.

Meredith Knight is a contributor to the human genetics section for Genetic Literacy Project and a freelance science and health writer in Austin, Texas. Follow her @meremereknight.

See more here:
Evolution and war: The 'deep roots' theory of human violence - Genetic Literacy Project

In BriefResearchers have identified a single gene deletion in E. colibacteria that influence longevity in C. elegans worms. This pointsto the role of gut bacteria in life extension and points to thepossibility of a life-extending probiotic in the future.

Researchers at the Baylor College of Medicine have found the key to longevity in Caenorhabditis elegans (C. elegans) worms and maybe, someday, humans. The team noticed that genetically identical worms would occasionally live for much longer, and looked to their gut bacteria to find the answer. They discovered that a strain of E. coli with a single gene deletion might be the reason that its hosts lives were being significantly extended.

This study is one among a number of projects that focus on the influence of the microbiome the community of microbes which share the body of the host organism on longevity. Ultimately, the goal of this kind of research is to develop probiotics that could extend human life. Ive always studied the molecular genetics of aging, Meng Wang, one of the researchers who conducted the study, told The Atlantic. But before, we always looked at the host. This is my first attempt to understand the bacterias side.

Even in cases like this, where it seems fairly obvious that the microbiome is influencing longevity, parsing out the details of how and why this happens among a tremendous variety of chemicals and microbe species is extremely complex. The team, in this case, was successful because they simplified the question and focused on a single relationship.

Genetically engineering bacteria to support and improve human health and even to slow aging and turning it into a usable, life-extending probiotic wont be easy. It is extremely difficult to make bacteria colonize the gut in a stable manner, which is a primary challenge in this field. The team, in this case, is looking to the microbiome, because the organisms used would be relatively safe to use because they would originate in the gut.

Clearly, researchers dont know yet whether these discoveries will be able to be applied to people, though it seems promising. Despite the obvious differences between the tiny C. elegans worm and us, its biology is surprisingly similar; many treatments that work well in mice and primates also work in the worm. The team will begin experiments along these same lines with mice soon.

Other interesting and recent research hoping to stop or slow the march of time includes work with induced pluripotent stem (iPS) cells, antioxidants that target the mitochondria, and even somewhat strangework with cord blood. It seems very likely that we wont have a single solution offering immortality anytime soon, but instead a range of treatment options that help to incrementally hold back time. And, with an improving quality of life, this kind of life extension sounds promising.

More:
This Study Could Help Extend the Human Lifespan - Futurism

Its been 10 years sinceMichael Wiglerhad a breakthrough revelation in autism geneticsone that arguably launched the field as we know it.

In April 2007, Wigler and his then colleague,Jonathan Sebat, reported that de novo mutationsthose that arise spontaneously instead of being inheritedoccur more often in people with autism than in typical people. The mutations they noted were in the form of copy number variants (CNVs), deletions or duplications of long stretches of DNA. CNVs crop up frequently in cancer, an earlier focus of Wiglers work. But his find that they are also involved in autism came as a surprise to those in the field. Genetics was striking out with other efforts based on transmission and inheritance, Wigler says. In that vacuum, the new idea was quickly embraced.

The discovery fast led to further advances. Focusing primarily onde novomutations, three teams of scientists, including one led by Wigler, began hunting for genes that contribute to autism. Their approach was efficient: Rather than looking at the entire genome, they scoured the 2 percent that encodes proteins, called theexome. And they looked specifically at simplex families, which have a single child with autism and unaffected parents and siblings. The premise was that comparing the exomes of the family members might exposede novomutations in the child with autism. The approachyielded a bumper crop: Based on data from more than 600 families, the teams together predicted that there are hundreds of autism genes. They identified six as leading candidates. Some of the genes identified at the time CHD8,DYRK1A,SCN2A quickly became hot areas of research.

In 2014, the number of strong candidates jumped higher. In two massive studies analyzing the sequences of more than 20,000 people, researchers linked 50 genes to autism with high confidence. Wiglers team looked at simplex families and found rarede novomutations in 27 genes. In the second study, researchers screened for both inherited andde novomutations and implicated 33 genes. The two studies identified 10 genes in common.

Two years ago, the tally of autism gene candidates shot up again. Deploying statistical wizardry to combine the data onde novoand inherited mutations, along with CNV data from theAutism Genome Project, researchers pinpointed 65 genes and six CNVsas being key to autism. They also identified 28 genes that they could say with near certainty are autism genes.

For so long, weve been saying if we could just find these genes, wed be able to really make some headway, saysStephan Sanders, assistant professor of psychiatry at the University of California, San Francisco, who co-led the study. Suddenly, youve got this list of 65-plus genes, which we know have a causative role in autism, and as a foundation for going forward, its amazing.

These advances establish beyond doubt that autism is firmly rooted in biology. More and more, we are erasing this idea of autism being a stigmatizing psychiatric disorder, and I think this is true for the whole of psychiatry, Sanders says. These are genetic disorders; this is a consequence of biology, which can be understood, and where traction can be made.

This is just the start, however. As scientists enter the next chapter of autism genetics, they are figuring out how to build on what they have learned, using better sequencing tools and statistics, bigger datasets and more robust models. For example, they are looking for common variantswhich are found in more than 1 percent of the population but may contribute to autism when inherited en masse. And they are also starting to look beyond the exome to the remaining 98 percent of the genome they have largely neglected thus far.

Most of the genetic advances fall into a category of large-effect-sizede novovariants, which is only one piece of the puzzle, saysDaniel Geschwind, professor of human genetics at the University of California, Los Angeles. Its an important piece, but one that still cannot explain why autism clusters in families, for instance, or why close relatives of people with autism often share some of the conditions traits.

So how much of autisms genetic architecture have scientists uncovered? Current estimates suggest that rare mutations, whetherde novoor inherited, contribute to the condition somewhere between 10 and 30 percent of the time. Before the recent spate of discoveries, the proportion of individuals whose autism had a known genetic cause was only 2 to 3 percentmuch of that from rare related genetic syndromes, such asfragile X syndromeand tuberous sclerosis complex, which stem from mutations in a single known gene. These syndromes often involve some core features of autism, along with their own set of characteristic traits, and intellectual disability.

Two generations ago, at least 75 percent of the time autism was comorbid with severe intellectual disability and other neurodevelopmental abnormalities, saysMark Daly, associate professor of medicine at Harvard University. It was also a much rarer diagnosis.

The large increase in diagnoses in recent decades overwhelmingly reflects cases at the mild end of the spectrum, Daly says, creating a new challenge. The genetics of autism has us wrestling with the fact that rare mutations, and especially these spontaneously arising ones, are the strongest risk factors, he says. But at the same time, theres a majority of cases now that dont have any of those high-impact risk factors.

Instead, much of the risk in these instances likely comes from common variants, which have small effects on their own, but can add up to increase overall risk. Researchers have tried to identify those relevant to autism using genome-wide association studies (GWAS), which compare the genomes of people with and without a condition to find differences in single-letter swaps of DNA called single nucleotide polymorphisms.

Because common variants have small effects individually, they are difficult to find, but multiple studies suggest that theyplay a major rolein autism risk. In a 2014 study, for instance, researchers used statistical tools to estimate the heritability of autism from the amount of common variation shared by unrelated people with autism. They applied the method to data from more than 3,000 people in Swedens national health registry. Their calculations indicated thatcommon variants account for 49 percentof the risk for autism in the general population; rare variants, equal partsde novoand inherited, explain 6 percent. Some scientists dispute these figures, but its clear that common variants, rare inherited variants and spontaneous mutations all play a part in autism.

Wigler says he is skeptical of using GWAS studies for autism precisely because they focus on common variants. Most of the disorders that will cause pain and suffering and require expensive treatments, if theyre genetic, are caused by rare variants that are not going to stay around in the population, he says.

Common variants may turn out to be more relevant at the milder end of the spectrum than in those who are severely affected. The people who havede novomutations, en masse, tend to have lower intelligence quotients and more cognitive problems, Sanders says.

Researchers are grappling with how to fit these pieces together: Finding and diagnosing rare variants linked to severe outcomes is important, but so is unraveling how the core traits of autism relate to other psychiatric conditions and manifest in the general population. Both goals are important, and they shouldnt be seen as at odds with each other, Daly says. In fact, a study published in May reported thatrare and common variants can combineto increase an individuals risk.

The landscape of autism genetics becomes even more complex when considering the sheer number of genes that could be involvedsome researchers estimate up to a thousandand the fact that many high-confidence autism genes are also associated with other conditions, ranging from intellectual disability andepilepsyto schizophrenia and congenital heart disease.

This many-to-one and one-to-many relationship is not surprising, Sanders says. But it does mean there are probably no unique autism genes per se. But I could flip that round and say weve not found anything which is a pure intellectual disability or schizophrenia gene [either]; on a fundamental level, these disorders seem to be related, he says. If I was to say, Can we find something which contributes more to autism than other disorders? then I think the answers yes. The genes that seem particularly tied to autism could offer important clues about the conditions biology.

The genes identified so far have hinted at a handful of underlying mechanisms that contribute to autism. Most of them seem to be involved in three broad categories of tasks: maintaining the function ofsynapses, or the connections between neurons; controlling the expression of genes; and modifying chromatin, structures of DNA wound around protein spools called histones. Chromatin determines which stretches of DNA can be read and so influences gene expression.

The idea of a brain condition originating with atypical neuronal connections made logical sense from the start. There had been a lot of interest in the synapse, Sanders says. But the candidates that control gene expression only emerged in the genetic studies. Two genes that consistently top the high-confidence listsCHD8 and SCN2Awere both somewhat of a surprise. CHD8 encodes a chromatin regulator that controls the expression of thousands of other genes. SCN2A codes for a sodium channel and had primarily been associated with infantile seizures.

Using gene expression maps, such as theBrainSpan Atlas, researchers have traced when and where autism genes are active in the brain. They have found that many of the genes, CHD8 and SCN2A included, are expressed in parts of the cortex during mid- to late fetal developmentwhich happens to be the peak period when neurons are forming. We dont really understand it yet, but theyre more likely than not to disrupt fetal brain development in mid-gestation, Geschwind says. That timing suggests they interfere with processes that are critical to setting up the cortex, including which types of cells form and where in the brain they migrate. If the cortex isnt set up right, he says, you create ongoing problems with how neurons communicate, among other important functions. Within the next few years, he says, researchers will have a refined understanding of the neurons and circuits affected.

Work in animal and cell models reveals similar problems with the genesis, structure and fate of new neurons and the connections between them. In some cell and animal models of syndromic forms of autism, scientists have managed to at least partially correct some of these problems with drugs. The unrealized promise of these findings is that some traits of autism may ultimately prove reversible, even in adults.

The idea that theres something plastic here, not set in stone at birth, is very important, saysMatthew State, chair of psychiatry at the University of California, San Francisco, and lead investigator on many of the big autism genetics studies.

In the meantime, genetic discoveries have delivered some immediate benefits for people with the condition. If you go into a clinic today, theres about a 10 percent chance of you getting a genetic diagnosis, and I would expect to find evidence which was suggestive in about another 5 to 10 percent, Sanders says. We cant then turn round and say, Heres your cure, but what we can do, at least, is put people in touch with other people with that same mutation. Becoming part of such a group gives people a better idea about what the future holds for them and provides them with support and understanding.

Advocacy groups can lobby researchers and funding bodies, contribute to research on their condition and help find participants for clinical trialswhich, by grouping people according to their underlying genetics, would then have a greater chance of success. It becomes very empowering, saysJoseph Buxbaum, director of the Seaver Autism Center for Research and Treatment in New York.

Genetic diagnoses can also help families make decisions about family planning and treatment options. For example, deletion of a region on chromosome 17, called 17q12, is associated with autism and schizophrenia, but treating someone who has this CNV with certain mood stabilizers or antipsychotics could be dangerous: It is also associated with renal failure and adult-onset diabetes, which the drugs would exacerbate. Whats more, certain mutations increase therisk for some types of cancer. Knowing those mutations can be very helpful in those cases, not just in treating autism, but in treating the patient more broadly, Geschwind says.

Debates abound on how best to move the field forward, but one thing most researchers agree on is the need to identify more mutations linked to autism. Theres great benefit now in just doing more exome sequencing, Sanders says. Theres more genes to be found: Those will hopefully help patients; theyll also give us more of an understanding of what autism is.

Much of the variation that predisposes someone to autism, however, may lie in noncoding regions. If half of the variants are outside of the coding region, we need to know how to interpret them, Wigler says. For that reason alone, we have to study that region. Plus, were going to learn an enormous amount of biology in the process.

Noncoding regions make up the dark genome, which is about 98 percent of the whole. Because of the cost and effort involved in sequencing the whole genome, most autism researchers have stayed focused on exomes, until recently. Several teams are now sequencing whole genomes of people with autism, with the aim of identifying risk variants in these noncoding regions. Whole-genome sequencing inevitably will overtake exome sequencing, Sanders says. Its just a question economically of whether its moment is now, or in two years, or five years. Right now, thats a hard question to answer.

In March, researchers in Canada reported results from the largest set of whole genomes of people with autism to date. They sequenced the whole genomes of more than 5,000 individuals, about half of whom have autism. Among the61 variants the researchers identified, 18 had not beenfirmly linked to autismbefore. The team found that many of the CNVs in people with autism rest in noncoding regions.

Some teams are applying other resources, such as gene co-expression maps and protein-protein interaction networks, to understanding the underlying biology of the condition. These networks are only likely to become more powerful as researchers uncover more risk genes for autism. The question is how to integrate all that genetic data with other -omics data, and network-type approaches are probably going to be critical there, Geschwind says.

Most autism research arising from gene discovery is focused on repercussions at the molecular and cellular levels, but theres an important gap from there to whole circuits and behavior. Ultimately, the value of genetics is very likely to play out through an improved understanding of circuit-level function and anatomy, State says.

Stem cells and emerging technologies such as brain organoidsso called mini-brains in a dishcould afford researchers a prime opportunity to study the effects of genetic variation in human neurons. Faced with the limitations of mouse models in studying a condition characterized by behavioral problems, some teams are alsoturning to monkeys, which enable them to study more complex social interactions. Something we should be doing for the future is taking the precise mutations we find in humans and making those in primates, Wigler says.

These days, Wigler is on to another big idea: risk modifiers. Rare variants strongly associated with autism also occur in people without autismespecially women. Researchers know that mutations can contribute to autism by amplifying or attenuating the effects of other genes, so its feasible that two mutations could cancel each other out. But few teams have looked into these combinations as yet. People talk about autism as being an additive disorder, Wigler says, but nobodys really looking at additivity.

This idea brings him to a possible experiment: Take two mutations that individually have damaging effects, and introduce them both into mouse or monkey. Having the combination would be predicted to be worse than having either mutation alone. But what if the net result is correction? Wigler asks. Then we know modifiers exist. Theres not much of that kind of scientific exploration happening now.

A finding of that nature would herald a whole new wave of advances. It might also help to explain why the mutations identified so far vary in their effector what geneticists call penetranceonly sometimes resulting in autism. And it might help researchers develop therapies. If we ever saw a self-correcting defect in two mutations in autism, Wigler says, I would stand up and cheer.

This story wasoriginally publishedonSpectrum.

See more here:
Using Big Data to Hack Autism - Scientific American