Category Archives: Human Genetics

A better understanding of the cause of autism may come from an unlikely source,eurological studies of the fruit fly. Neuroscientists working in the biology department at the University of Nevada, Reno have identified a new genetic mechanism they believe is responsible for disruption of the brain pathways connecting the left and right hemispheres of the brain; which has separately been linked to autism.

This is an exciting find, Thomas Kidd, associate professor in the University's biology department, said. In the one striking mutant, called commissureless or comm, there are almost no connections between the two sides of the fruit flys nervous system.

The fruit fly nervous system research was conducted in Kidds lab over several years. Fruit flies have brains and nerve cords that form using molecules surprisingly similar to those in human brains and spinal cords. The study, published in the scientific journal PLOS Genetics, shows that the human gene, called PRRG4, functions the same way as the fruit fly Comm at the molecular level, regulating which signals neurons can respond to in their environment.

The Comm gene was thought to be unique to insects but our work shows that it is not, Elizabeth Justice, lead author of the PLOS Genetics article and a former postdoctoral neuroscience researcher in Kidds lab, said.

Comm is required for nerve fiber guidance and synapse formation in the fly, so PRRG4 could contribute to the autistic symptoms of WAGR by disturbing either of these processes in the developing human brain.

PRRG4 appears very likely to control how nerve fibers link the two sides of the nervous system in humans, and this is being actively tested, Sarah Barnum, a former undergraduate researcher in the Kidd lab who worked on the project, said.

MIssing GenesThe fruit fly has no left-right connections when two copies of the gene are missing. In humans there is a condition called WAGR syndrome in which a group of genes are missing on one chromosome. When the gene Kidds team is interested in, the PRRG4 gene, is missing, autistic symptoms are observed.

The function of the gene was obscure but we now show that it can regulate whether key proteins make it to the cell surface when neuronal wiring is navigating, Kidd said. This would tie it to our colleague Jeff Hutslers work that indicates autistic changes start in utero.

Jeffrey Hutsler, in the department of Psychology, and the Cognitive and BrainSciences Program and also in the Universitys neuroscience program, is an expert on autism and split-brain patients.

Bridges in the brainSplit brain patients have the connections between the left and right brain hemispheres severed, usually to relieve epilepsy symptoms. The disrupted structure is called the corpus callosum, a bridge consisting of millions of nerve fibers that allows constant exchange of information between the two sides of the brain. The corpus callosum forms during pregnancy and subtle disruptions to the structure are associated with developing autism.

Hutsler, who was not involved in the study, is also very excited by the work.

We know that brain wiring is altered in autism spectrum disorders and our own work has found similarities in the way visual information is integrated between the two brain hemispheres of split-brain patients and autistic individuals, Hutsler said. It is therefore very plausible that PRRG4 will be found to play a part in the altered formation of the corpus callosum in individuals with autism.

The journal which published the study, PLOS Genetics, commissioned a perspective on the article because of its significance.

Understanding the genetic mechanisms underlying the assembly of brain circuits is likely to be essential to the design of new diagnostic tools and therapeutic strategies for Autistic Spectrum Disorders, Jimena Berni wrote in the perspective, explaining that the study links the genetic alterations and neural circuitry development revealing a novel role for the PRRG4 gene as a regulator.

The University of Nevada, Reno study will inspire members of several diverse fields and drive research forward in several ways, including:

1. Axon (nerve fibers) guidance a range of physical interactors have been identified for PRRG proteins and these provide promising new avenues for investigation in all axon guidance systems.

2. Vertebrate brain development and human genetics the PRRG genes are expressed during brain development and in adults, but detailed surveys of expression patterns are lacking. Examination of key midline crossing structures such as the floor plate of the spinal cord and the corpus callosum is an obvious next step, but many other brain structures should be examined.

3. Yeast protein trafficking The findings offer the intriguing possibility that yeast genetics can be used to identify the mechanisms by which Rcr/Comm/PRRG proteins regulate protein trafficking to the cell surface.

The PLOS Genetics article is available on the Public Library of Science website.

The research was funded by the National Institute of Neurological Disorders and Stroke. The Kidd lab was part of a $10 millionCenter for Biomedical Research Excellence Project in Cell Biology of Signalingat the University, which is funded by the National Institute of Health's Institute of General Medical Sciences. Kidd is also a fellow in the Universitys Research and Innovation Office.

Both Jeff Hutsler Kidd are part of the Universitys Integrative Neuroscience program. In 2010, Hutsler received the Slifka-Ritvo Award for Innovation in Autism Research from International Society for Autism Research.

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Split-brain fruit fly research gives insight into autism - Nevada Today

In 1944, a Columbia University doctoral student in genetics named Evelyn Witkin made a fortuitous mistake. During her first experiment in a laboratory at Cold Spring Harbor, in New York, she accidentally irradiated millions of E. coli with a lethal dose of ultraviolet light. When she returned the following day to check on the samples, they were all deadexcept for one, in which four bacterial cells had survived and continued to grow. Somehow, those cells were resistant to UV radiation. To Witkin, it seemed like a remarkably lucky coincidence that any cells in the culture had emerged with precisely the mutation they needed to surviveso much so that she questioned whether it was a coincidence at all.

Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

For the next two decades, Witkin sought to understand how and why these mutants had emerged. Her research led her to what is now known as the SOS response, a DNA repair mechanism that bacteria employ when their genomes are damaged, during which dozens of genes become active and the rate of mutation goes up. Those extra mutations are more often detrimental than beneficial, but they enable adaptations, such as the development of resistance to UV or antibiotics.

The question that has tormented some evolutionary biologists ever since is whether nature favored this arrangement. Is the upsurge in mutations merely a secondary consequence of a repair process inherently prone to error? Or, as some researchers claim, is the increase in the mutation rate itself an evolved adaptation, one that helps bacteria evolve advantageous traits more quickly in stressful environments?

The scientific challenge has not just been to demonstrate convincingly that harsh environments cause nonrandom mutations. It has also been to find a plausible mechanism consistent with the rest of molecular biology that could make lucky mutations more likely. Waves of studies in bacteria and more complex organisms have sought those answers for decades.

The latest and perhaps best answerfor explaining some kinds of mutations, anywayhas emerged from studies of yeast, as reported in June in PLOS Biology. A team led by Jonathan Houseley, a specialist in molecular biology and genetics at the Babraham Institute in Cambridge, proposed a mechanism that drives more mutation specifically in regions of the yeast genome where it could be most adaptive.

Its a totally new way that the environment can have an impact on the genome to allow adaptation in response to need. It is one of the most directed processes weve seen yet, said Philip Hastings, professor of molecular and human genetics at Baylor College of Medicine, who was not involved in the Houseley groups experiments. Other scientists contacted for this story also praised the work, though most cautioned that much about the controversial idea was still speculative and needed more support.

Rather than asking very broad questions like are mutations always random? I wanted to take a more mechanistic approach, Houseley said. He and his colleagues directed their attention to a specific kind of mutation called copy number variation. DNA often contains multiple copies of extended sequences of base pairs or even whole genes. The exact number can vary among individuals because, when cells are duplicating their DNA before cell division, certain mistakes can insert or delete copies of gene sequences. In humans, for instance, 5 to 10 percent of the genome shows copy number variation from person to personand some of these variations have been linked to cancer, diabetes, autism and a host of genetic disorders. Houseley suspected that in at least some cases, this variation in the number of gene copies might be a response to stresses or hazards in the environment.

Jonathan Houseley leads a team that studies genome change at the Babraham Institute in Cambridge. Based on their studies of yeast, they recently proposed a mechanism that would increase the odds for adaptive mutations in genes that are actively responding to environmental challenges.

Jon Houseley/QUANTA MAGAZINE

In 2015, Houseley and his colleagues described a mechanism by which yeast cells seemed to be driving extra copy number variation in genes associated with ribosomes, the parts of a cell that synthesize proteins. However, they did not prove that this increase was a purposefully adaptive response to a change or constraint in the cellular environment. Nevertheless, to them it seemed that the yeast was making more copies of the ribosomal genes when nutrients were abundant and the demand for making protein might be higher.

Houseley therefore decided to test whether similar mechanisms might act on genes more directly activated by hazardous changes in the environment. In their 2017 paper, he and his team focused on CUP1, a gene that helps yeast resist the toxic effects of environmental copper. They found that when yeast was exposed to copper, the variation in the number of copies of CUP1 in the cells increased. On average, most cells had fewer copies of the gene, but the yeast cells that gained more copiesabout 10 percent of the total population became more resistant to copper and flourished. The small number of cells that did the right thing, Houseley said, were at such an advantage that they were able to outcompete everything else.

But that change did not in itself mean much: If the environmental copper was causing mutations, then the change in CUP1 copy number variation might have been no more than a meaningless consequence of the higher mutation rate. To rule out that possibility, the researchers cleverly re-engineered the CUP1 gene so that it would respond to a harmless, nonmutagenic sugar, galactose, instead of copper. When these altered yeast cells were exposed to galactose, the variation in their number of copies of the gene changed, too.

The cells seemed to be directing greater variation to the exact place in their genome where it would be useful. After more work, the researchers identified elements of the biological mechanism behind this phenomenon. It was already known that when cells replicate their DNA, the replication mechanism sometimes stalls. Usually the mechanism can restart and pick up where it left off. When it cant, the cell can go back to the beginning of the replication process, but in doing so, it sometimes accidentally deletes a gene sequence or makes extra copies of it. That is what causes normal copy number variation. But Houseley and his team made the case that a combination of factors makes these copying errors especially likely to hit genes that are actively responding to environmental stresses, which means that they are more likely to show copy number variation.

The key point is that these effects center on genes responding to the environment, and that they could give natural selection extra opportunities to fine-tune which levels of gene expression might be optimal against certain challenges. The results seem to present experimental evidence that a challenging environment could galvanize cells into controlling those genetic changes that would best improve their fitness. They may also seem reminiscent of the outmoded, pre-Darwinian ideas of the French naturalist Jean-Baptiste Lamarck, who believed that organisms evolved by passing their environmentally acquired characteristics along to their offspring. Houseley maintains, however, that this similarity is only superficial.

What we have defined is a mechanism that has arisen entirely through Darwinian selection of random mutations to give a process that stimulates nonrandom mutations at useful sites, Houseley said. It is not Lamarckian adaptation. It just achieves some of the same ends without the problems involved with Lamarckian adaptation.

Ever since 1943, when the microbiologist Salvador Luria and the biophysicist Max Delbrck showed with Nobel prize-winning experiments that mutations in E. coli occur randomly, observations like the bacterial SOS response have made some biologists wonder whether there might be important loopholes to that rule. For example, in a controversial paper published in Nature in 1988, John Cairns of Harvard and his team found that when they placed bacteria that could not digest the milk sugar lactose in an environment where that sugar was the sole food source, the cells soon evolved the ability to convert the lactose into energy. Cairns argued that this result showed that cells had mechanisms to make certain mutations preferentially when they would be beneficial.

Budding yeast (S. cerevisiae) grow as colonies on this agar plate. If certain recent research is correct, a mechanism that helps to repair DNA damage in these cells may also promote more adaptive mutations, which could help the cells to evolve more quickly under harsh circumstances.

Jon Houseley/QUANTA MAGAZINE

Experimental support for that specific idea eventually proved lacking, but some biologists were inspired to become proponents of a broader theory that has come to be known as adaptive mutation. They believe that even if cells cant direct the precise mutation needed in a certain environment, they can adapt by elevating their mutation rate to promote genetic change.

The work of the Houseley team seems to bolster the case for that position. In the yeast mechanism theres not selection for a mechanism that actually says, This is the gene I should mutate to solve the problem, said Patricia Foster, a biologist at Indiana University. It shows that evolution can get speeded up.

Hastings at Baylor agreed, and praised the fact that Houseleys mechanism explains why the extra mutations dont happen throughout the genome. You need to be transcribing a gene for it to happen, he said.

Adaptive mutation theory, however, finds little acceptance among most biologists, and many of them view the original experiments by Cairns and the new ones by Houseley skeptically. They argue that even if higher mutation rates yield adaptations to environmental stress, proving that the higher mutation rates are themselves an adaptation to stress remains difficult to demonstrate convincingly. The interpretation is intuitively attractive, said John Roth, a geneticist and microbiologist at the University of California, Davis, but I dont think its right. I dont believe any of these examples of stress-induced mutagenesis are correct. There may be some other non-obvious explanation for the phenomenon.

I think [Houseleys work] is beautiful and relevant to the adaptive mutation debate, said Paul Sniegowski, a biologist at the University of Pennsylvania. But in the end, it still represents a hypothesis. To validate it more certainly, he added, theyd have to test it in the way an evolutionary biologist wouldby creating a theoretical model and determining whether this adaptive mutability could evolve within a reasonable period, and then by challenging populations of organisms in the lab to evolve a mechanism like this.

Notwithstanding the doubters, Houseley and his team are persevering with their research to understand its relevance to cancer and other biomedical problems. The emergence of chemotherapy-resistant cancers is commonplace and forms a major barrier to curing the disease, Houseley said. He thinks that chemotherapy drugs and other stresses on tumors may encourage malignant cells to mutate further, including mutations for resistance to the drugs. If that resistance is facilitated by the kind of mechanism he explored in his work on yeast, it could very well present a new drug target. Cancer patients might be treated both with normal courses of chemotherapy and with agents that would inhibit the biochemical modifications that make resistance mutations possible.

We are actively working on that, Houseley said, but its still in the early days.

Original story reprinted with permission from Quanta Magazine, an editorially independent publication of the Simons Foundation whose mission is to enhance public understanding of science by covering research developments and trends in mathematics and the physical and life sciences.

Link:
Bacteria May Rig Their DNA to Speed Up Evolution - WIRED

Scientists recently used a gene-editing tool to fix a mutation in a human embryo. Around the world, researchers are chasing cures for other genetic diseases.

Now that the gene-editing genie is out of the bottle, what would you wish for first?

Babies with perfect eyes, over-the-top intelligence, and a touch of movie star charisma?

Or a world free of disease not just for your family, but for every family in the world?

Based on recent events, many scientists are working toward the latter.

Earlier this month, scientists from the Oregon Health & Science University used a gene editing tool to correct a disease-causing mutation in an embryo.

The technique, known as CRISPR-Cas9, fixed the mutation in the embryos nuclear DNA that causes hypertrophic cardiomyopathy, a common heart condition that can lead to heart failure or cardiac death.

This is the first time that this gene-editing tool has been tested on clinical-quality human eggs.

Had one of these embryos been implanted into a womans uterus and allowed to fully develop, the baby would have been free of the disease-causing variation of the gene.

This type of beneficial change would also have been passed down to future generations.

None of the embryos in this study were implanted or allowed to develop. But the success of the experiment offers a glimpse at the potential of CRISPR-Cas9.

Still, will we ever be able to gene-edit our world free of disease?

According to the Genetic Disease Foundation, there are more than 6,000 human genetic disorders.

Scientists could theoretically use CRISPR-Cas9 to correct any of these diseases in an embryo.

To do this, they would need an appropriate piece of RNA to target corresponding stretches of genetic material.

The Cas9 enzyme cuts DNA at that spot, which allows scientists to delete, repair, or replace a specific gene.

Some genetic diseases, though, may be easier to treat with this method than others.

Most people are focusing, at least initially, on diseases where there really is only one gene involved or a limited number of genes and theyre really well understood, Megan Hochstrasser, PhD, science communications manager at the Innovative Genomics Institute in California, told Healthline.

Diseases caused by a mutation in a single gene include sickle cell disease, cystic fibrosis, and Tay-Sachs disease. These affect millions of people worldwide.

These types of diseases, though, are far outnumbered by diseases like cardiovascular disease, diabetes, and cancer, which kill millions of people across the globe each year.

Genetics along with environmental factors also contribute to obesity, mental illness, and Alzheimers disease, although scientists are still working on understanding exactly how.

Right now, most CRISPR-Cas9 research focuses on simpler diseases.

There are a lot of things that have to be worked out with the technology for it to get to the place where we could ever apply it to one of those polygenic diseases, where multiple genes contribute or one gene has multiple effects, said Hochstrasser.

Although designer babies gain a lot of media attention, much CRISPR-Cas9 research is focused elsewhere.

Most people who are working on this are not working in human embryos, said Hochstrasser. Theyre trying to figure out how we can develop treatments for people that already have diseases.

These types of treatments would benefit children and adults who are already living with a genetic disease, as well as people who develop cancer.

This approach may also help the 25 million to 30 million Americans who have one of the more than 6,800 rare diseases.

Gene editing is a really powerful option for people with rare disease, said Hochstrasser. You could theoretically do a phase I clinical trial with all the people in the world that have a certain [rare] condition and cure them all if it worked.

Rare diseases affect fewer than 200,000 people in the United States at any given time, which means there is less incentive for pharmaceutical companies to develop treatments.

These less-common diseases include cystic fibrosis, Huntingtons disease, muscular dystrophies, and certain types of cancer.

Last year researchers at the University of California Berkeley made progress in developing an ex vivo therapy where you take cells out of a person, modify them, and put them back into the body.

This treatment was for sickle cell disease. In this condition, a genetic mutation causes hemoglobin molecules to stick together, which deforms red blood cells. This can lead to blockages in the blood vessels, anemia, pain, and organ failure.

Researchers used CRISPR-Cas9 to genetically engineer stem cells to fix the sickle cell disease mutation. They then injected these cells into mice.

The stem cells migrated to the bone marrow and developed into healthy red blood cells. Four months later, these cells could still be found in the mices blood.

This is not a cure for the disease, because the body would continue to make red blood cells that have the sickle cell disease mutation.

But researchers think that if enough healthy stem cells take root in the bone marrow, it could reduce the severity of disease symptoms.

More work is needed before researchers can test this treatment in people.

A group of Chinese researchers used a similar technique last year to treat people with an aggressive form of lung cancer the first clinical trial of its kind.

In this trial, researchers modified patients immune cells to disable a gene that is involved in stopping the cells immune response.

Researchers hope that, once injected into the body, the genetically edited immune cells will mount a stronger attack against the cancer cells.

These types of therapies might also work for other blood diseases, cancers, or immune problems.

But certain diseases will be more challenging to treat this way.

If you have a disorder of the brain, for example, you cant remove someones brain, do gene editing and then put it back in, said Hochstrasser. So we have to figure out how to get these reagents to the places they need to be in the body.

Not every human disease is caused by mutations in our genome.

Vector-borne diseases like malaria, yellow fever, dengue fever, and sleeping sickness kill more than 1 million people worldwide each year.

Many of these diseases are transmitted by mosquitoes, but also by ticks, flies, fleas, and freshwater snails.

Scientists are working on ways to use gene editing to reduce the toll of these diseases on the health of people around the world.

We could potentially get rid of malaria by engineering mosquitoes that cant transmit the parasite that causes malaria, said Hochstrasser. We could do this using the CRISPR-Cas9 technique to push this trait through the entire mosquito population very quickly.

Researchers are also using CRISPR-Cas9 to create designer foods.

DuPont recently used gene editing to produce a new variety of waxy corn that contains higher amounts of starch, which has uses in food and industry.

Modified crops may also help reduce deaths due to malnutrition, which is responsible for nearly half of all deaths worldwide in children under 5.

Scientists could potentially use CRISPR-Cas9 to create new varieties of food that are pest-resistant, drought-resistant, or contain more micronutrients.

One benefit of CRISPR-Cas9, compared to traditional plant breeding methods, is that it allows scientists to insert a single gene from a related wild plant into a domesticated variety, without other unwanted traits.

Gene editing in agriculture may also move more quickly than research in people because there is no need for years of lab, animal, and human clinical trials.

Even though plants grow pretty slowly, said Hochstrasser, it really is quicker to get [genetically engineered plants] out into the world than doing a clinical trial in people.

Safety and ethical concerns

CRISPR-Cas9 is a powerful tool, but it also raises several concerns.

Theres a lot of discussion right now about how best to detect so-called off-target effects, said Hochstrasser. This is what happens when the [Cas9] protein cuts somewhere similar to where you want it to cut.

Off-target cuts could lead to unexpected genetic problems that cause an embryo to die. An edit in the wrong gene could also create an entirely new genetic disease that would be passed onto future generations.

Even using CRISPR-Cas9 to modify mosquitoes and other insects raises safety concerns like what happens when you make large-scale changes to an ecosystem or a trait in a population that gets out of control.

There are also many ethical issues that come with modifying human embryos.

So will CRISPR-Cas9 help rid the world of disease?

Theres no doubt that it will make a sizeable dent in many diseases, but its unlikely to cure all of them any time soon.

We already have tools for avoiding genetic diseases like early genetic screening of fetuses and embryos but these are not universally used.

We still dont avoid tons of genetic diseases, because a lot of people dont know that they harbor mutations that can be inherited, said Hochstrasser.

Some genetic mutations also happen spontaneously. This is the case with many cancers that result from environmental factors such as UV rays, tobacco smoke, and certain chemicals.

People also make choices that increase their risk of heart disease, stroke, obesity, and diabetes.

So unless scientists can use CRISPR-Cas9 to find treatments for these lifestyle diseases or genetically engineer people to stop smoking and start biking to work these diseases will linger in human society.

Things like that are always going to need to be treated, said Hochstrasser. I dont think its realistic to think we would ever prevent every disease from happening in a human.

Excerpt from:
Will Gene Editing Allow Us to Rid the World of Diseases? - Healthline

In collaboration with scientists from the U.K., Europe, Japan and the United States, researchers at the Human Genome Sequencing Center at Baylor College of Medicine have discovered a whole genome duplication during the evolution of spiders and scorpions. The study appears in BMC Biology.

Researchers have long been studying spiders and scorpions for both applied reasons, such as studying venom components for pharmaceuticals and silks for materials science, and for basic questions such as the reasons for the evolution and to understand the development and ecological success of this diverse group of carnivorous organisms.

As part of a pilot project for the i5K, a project to study the genomes of 5,000 arthropod species, the Human Genome Sequencing Center analyzed the genome of the house spider Parasteatoda tepidariorum - a model species studied in laboratories - and the Arizona bark scorpion Centruroides sculpturatus, - the most venomous scorpion in North America.

Analysis of these genomes revealed that spiders and scorpions evolved from a shared ancestor more than 400 million years ago, which made new copies of all of the genes in its genome, a process called whole genome duplication. Such an event is one of the largest evolutionary changes that can happen to a genome and is relatively rare during animal evolution.

Dr. Stephen Richards, associate professor in the Human Genome Sequencing Center, who led the genome sequencing at Baylor, said, "It is tremendously exciting to see rapid progress in our molecular understanding of a species that we coexist with on planet earth. Spider genome analysis is particularly tricky, and we believe this is one of the highest quality spider genomes to date."

Similarly, there also have been two whole genome duplications at the origin of vertebrates, fuelling long-standing debate as to whether the duplicated genes enabled new biological complexity in the evolution of the vertebrate lineage leading to mammals. The new finding of a whole genome duplication in spiders and scorpions therefore provides a valuable comparison to the events in vertebrates and could help reveal genes and processes that have been important to our own evolution.

"While most of the new genetic material generated by whole genome duplication is subsequently lost, some of the new gene copies can evolve new functions and may contribute to the diversification of shape, size, physiology and behavior of animals," said Dr. Alistair McGregor, professor of evolutionary developmental biology at Oxford Brookes University and lead author of the research. "Comparing the whole genome duplication in spiders and scorpions with the independent events in vertebrates reveals a striking similarity. In both cases, duplicated clusters of Hox genes have been retained. These are very important genes that regulate development of body structures in all animals, and therefore can cause evolutionary changes in animal body plans."

The study also found that the copies of spider Hox genes show differences in when and where they are expressed, suggesting they have evolved new functions.

McGregor explains that these changes may help clarify the evolutionary innovations in spiders and scorpions including specialized limbs and how they breathe, as well as the production of different types of venom and silk, which spiders use to capture and kill their prey.

"Many people fear spiders and scorpions, but this research shows what a beautiful part of the evolutionary tree they represent," said Dr. Richard Gibbs, director of the Human Genome Sequencing Center and the Wofford Cain Chair and professor of molecular and human genetics at Baylor.

"Costs have now dropped rapidly enough from tens of millions of dollars to merely a few thousand dollars for this genomic analyses to now be performed on any species," Richards said. "There is still so much more to learn about the life on earth around us, and I believe this result is just the beginning of understanding the molecular make up of spiders."

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Genome Sequencing Shows Spiders, Scorpions Share Ancestor - R & D Magazine

Mention of the movement to improve human genetics known as eugenics today evokes myriad horrors, including its association with forced sterilization, American racism, and Nazism.

But over a century after the beginning of the eugenics movement, scientist are carefully dipping back into the controversial research that looks at the influence genes have on certain behavioral characteristicssuch as intelligence, the likelihood of going to university, and even the amount of time a teen spends on social media.

While eugenicsthe term derived from Greek words for good and birthwas once used to justify entrenched inequality and systemic racism, some now argue that understanding the role of genetic predispositions can help achieve equal opportunities for all.

Francis Galton is widely known as the father of the eugenics. A younger cousin of Charles Darwin, Galton was the first to apply a version of Darwins theory of survival of the fittest to humans. In Hereditary Genius, published in 1869, Galton argued that everything from criminality to love of poetry was thought to be in the hereditary nature of humans, says James Tabery, a philosophy of science professor at the University of Utah. And, the theory went, that if society wanted less criminality and more poetry-loving people, then criminals would have to breed less and the people who love poetry breed more.

Of course, Galtons ideas didnt remain confined to academia. In the UK, the government passed the Mental Deficiency Act in 1913, which emphasized one principle; the separation of people with learning disabilities from the rest of the community. Though the act had near unanimous support, one of the MPs who condemned the law, Josiah Wedgwood, said: the spirit at the back of the Bill is not the spirit of charity, not the spirit of the love of mankind. It is a spirit of the horrible Eugenic Society which is setting out to breed up the working class as though they were cattle.

The US went even further. An estimated 60,000 people were sterilized in the US between the 1930s and 1970s. The federal backed procedures largely targeting the disabled, mentally ill, people of color, and the poor, were finally repealed in the 1970s. Eugenics was also used to justify the miscegenation laws that prevented people from different races from marrying, and it fed into anti-immigration rhetoric.

American sterilization efforts apparently inspired Adolf Hitler, and eugenics ideas helped inform Nazi Germanys final solution, where millions of Jewish, disabled, Roma, and LGBT people were murdered.

Following this litany of horrors, the 1940s saw a recoiling from eugenics, and a scientific undermining of the movements basic principles. Leading academics instead highlighted sociocultural explanations for differences and inequality.

This didnt mean that efforts to improve the human race through genetic selection were completely sidelined. The field slowly morphed into a field of science now known as human behavioral geneticsa field of science where researchers explore how genetics influences human behavior.

US behavioral geneticist David Lykken is a notable example. In 1998, Lykken advocated for a so-called parenting license. He argued that couples interested in having children should need to get a license, but those who were unmarried, unemployed, or disabled would be denied. The licensure of parenthood is the only real solution to the problem of sociopathy and crime, Lykken noted in his infamous paper.

In the last decade, however, a new approach to genetic research has been on the rise, one that argues for understanding its role in social mobility as a way to achieve greater equality for all. A recent study published in the journal Psychological Science last week tested the role genetics plays in parent-child association in education attainment.

Researchers found, as in previous studies, that the likelihood of a child going on to higher education is heavily influenced by their parents education. But while previously, this was largely attributed to environmental factorsthe argument being that parents who have been to university can provide more support in the early secondary years and advice when their child is applying for universitythe new study indicates that genetics may also play a role. Until now, Genetics is largely ignored in this dialogue, said Ziada Ayorech, the lead author of a recent study.

Ayorech, from the Institute of Psychiatry, Psychology and Neuroscience at Kings College London, and the other researchers looked at a sample of more than 6,000 families with identical and non-identical twins in the UK. They categorized the families into four groups:

The researchers used two methods to figure out to what extent social mobility is mediated by genetic differences. The first method is the traditional twin study design, in which researchers compare identical and non-identical twin pairs. If identical twin pairs were more similar in social mobility then non-identical twin pairs, then this was the first clue that genetics is important.

The second method used polygenic scores, a new scientific technique at the forefront of genetic analysis. Unlike the first method, which relies on comparisons between twin samples, polygenic scores is a predictive method based directly on DNA. Researchers looked at unrelated individuals, within the four groups, whose DNA they had information on. They looked at the extent to which genetic differencesthose differences in the letters of someones DNAcontribute to differences in social mobility.

With the first method, we found genetics played a substantial role. It explained 50% of differences in whether families were socially mobile or not, Ayorech explains. The second method mirrored the twin results, she adds.

The polygenic scoreswho had the most bits of DNA associated with higher levels of educationdiffered across these four groups. Those families that had the highest level of education had the highest polygenic scores. The lowest score was found in the families where the parents and children did not have higher education.

The researchers were keen to stress that though their results indicate that genetics played an important role in social mobility, genetics doesnt work in isolation from socioeconomic factors. Its always an interaction between the two, Ayorech says. Finding genetic influence on something that is traditionally seen as an environmental measure should highlight the fact that genes and environment are working together, Ayorech says. Even if something is highly genetically drivensuch as heightit doesnt mean genes are the only factor. Diet and their lifestyle also impact height.

The researchers also emphasize how their research could be used to promote social mobility. Ayorech suggests that even in a scenario where equal educational support has been provided for everyone, childrens outcomes will still vary. The students themselves will differ in the extent they take on these opportunities, in their aptitude, and in their appetite for education. Knowing the role genetics plays can lead to more tailored, personalized support to maximize the potential for each child, she argues.

She points towards preventative measures that are currently championed in medicine. People at risk of type two diabetes are put in prevention programs, where they get tailored, personalized support to reduce their risk. She says the same could be done in education. Children are already genetically screened for a whole host of conditions, and researchers could one day look at a genetics risk score that predicts learning disabilities. Rather then waiting until the child comes into school and then struggles, Ayorech says, early intervention can be put in place to provide more tailored support. We are a long way from applying this research effectively, Ayorech acknowledges. Researchers dont yet have the sophisticated tools to genetically screen a large enough sample size of children to do educational intervention.

Still, thats a fairly new idea, Tabery says. For the longest time, if anybody was introducing talk of genetics and intelligence with policy implications, they were doing it in the name of inequality, and these authors are trying to use it towards equality.

There lies the difference between genetics research in the 1930s and now, Tabery says: They are really going out of their way not to fall into the traps of the really reprehensible stuff.

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Mindful of eugenics' dark history, researchers are reexamining the genetics of social mobility - Quartz

Parsing the creatures 2 billion base pairs, Feschotte and his colleagues did stumble on something strange. We found some very weird transposons, he said. Because these oddball parasite sequences didnt appear in other mammals, they were likely to have invaded after bats diverged from other lineages, perhaps picked up from an insect snack some 30 to 40 million years ago. Whats more, they were incredibly active. Probably 20 percent or more of the bats genome is derived from this fairly recent wave of transposons, Feschotte said. It raised a paradox because when we see an explosion of transposon activity, wed predict an increase in size. Instead, the bat genome had shrunk. So we were puzzled.

There was only one likely explanation: Bats must have jettisoned a lot of DNA. When Kapusta joined Feschottes lab in 2011, her first project was to find out how much. By comparing transposons in bats and nine other mammals, she could see which pieces many lineages shared. These, she determined, must have come from a common ancestor. Its really like looking at fossils, she said. Researchers had previously assembled a rough reconstruction of the ancient mammalian genome as it might have existed 100 million years ago. At 2.8 billion base pairs, it was nearly human-size.

Next, Kapusta calculated how much ancestral DNA each lineage had lost and how much new material it had gained. As she and Feschotte suspected, the bat lineages had churned through base pairs, dumping more than 1 billion while accruing only another few hundred million. Yet it was the other mammals that made their jaws drop.

Mammals are not especially diverse when it comes to genome size. In many animal groups, such as insects and amphibians, genomes vary more than a hundredfold. By contrast, the largest genome in mammals (in the red viscacha rat) is only five times as big as the smallest (in the bent-wing bat). Many researchers took this to mean that mammalian genomes just dont have much going on. As Susumu Ohno, the noted geneticist and expert in molecular evolution, put it in 1969: In this respect, evolution of mammals is not very interesting.

But Kapustas data revealed that mammalian genomes are far from monotonous, having reaped and purged vast quantities of DNA. Take the mouse. Its genome is roughly the same size it was 100 million years ago. And yet very little of the original remains. This was a big surprise: In the end, only one-third of the mouse genome is the same, said Kapusta, who is now a research associate in human genetics at the University of Utah and at the USTAR Center for Genetic Discovery. Applying the same analysis to 24 bird species, whose genomes are even less varied than those of mammals, she showed that they too have a lively genetic history.

No one predicted this, said J. Spencer Johnston, a professor of entomology at Texas A&M University. Even those genomes that didnt change size over a huge period of time they didnt just sit there. Somehow they decided what size they wanted to be, and despite mobile elements trying to bloat them, they didnt bloat. So then the next obvious question is: Why the heck not?

Feschottes best guess points at transposons themselves. They provide a very natural mechanism by which gain provides the template to facilitate loss, he said. Heres how: As transposons multiply, they create long strings of nearly identical code. Parts of the genome become like a book that repeats the same few words. If you rip out a page, you might glue it back in the wrong place because everything looks pretty much the same. You might even decide the book reads just fine as is and toss the page in the trash. This happens with DNA too. When its broken and rejoined, as routinely happens when DNA is damaged but also during the recombination of genes in sexual reproduction, large numbers of transposons make it easy for strands to misalign, and that slippage can result in deletions. The whole array can collapse at once, Feschotte said.

This hypothesis hasnt been tested in animals, but there is evidence from other organisms. Its not so different from what were seeing in plants with small genomes, Leitch said. DNA in these species is often dominated by just one or two types of transposons that amplify and then get eliminated. The turnover is very dynamic: in 3 to 5 million years, half of any new repeats will be gone.

Thats not the case for larger genomes. What we see in big plant genomes and also in salamanders and lungfish is a much more heterogeneous set of repeats, none of which are present in [large numbers], Leitch said. She thinks these genomes must have replaced the ability to knock out transposons with a novel and effective way of silencing them. What they do is, they stick labels onto the DNA that signal to it to become very tightly condensed sort of squished so it cant be read easily. That alteration stops the repeats from copying themselves, but it also breaks the mechanism for eliminating them. So over time, Leitch explained, any new repeats get stuck and then slowly diverge through normal mutation to produce a genome full of ancient degenerative repeats.

Meanwhile, other forces may be at play. Large genomes, for instance, can be costly. Theyre energetically expensive, like running a big house, Leitch said. They also take up more space, which requires a bigger nucleus, which requires a bigger cell, which can slow processes like metabolism and growth. Its possible that in some populations, under some conditions, natural selection may constrain genome size. For example, female bow-winged grasshoppers, for mysterious reasons, prefer the songs of males with small genomes. Maize plants growing at higher latitudes likewise self-select for smaller genomes, seemingly so they can generate seed before winter sets in.

Some experts speculate that a similar process is going on in birds and bats, which may need small genomes to maintain the high metabolisms needed for flight. But proof is lacking. Did small genomes really give birds an advantage in taking to the skies? Or had the genomes of birds flightless dinosaur ancestors already begun to contract for some other reason, and did the physiological demands of flight then shrink the genomes of modern birds even more? We cant say whats cause and effect, Suh said.

Its also possible that genome size is largely a result of chance. My feeling is theres one underlying mechanism that drives all this variability, said Mike Lynch, a biologist at Indiana University. And thats random genetic drift. Its a principle of population genetics that drift whereby a genetic variant becomes more or less common just by sheer luck is stronger in small groups, where theres less variation. So when populations decline, such as when new species diverge, the odds increase that lineages will drift toward larger genomes, even if organisms become slightly less fit. As populations grow, selection is more likely to quash this trait, causing genomes to slim.

None of these models, however, fully explain the great diversity of genome forms. The way I think of it, youve got a bunch of different forces on different levels pushing in different directions, Gregory said. Untangling them will require new kinds of experiments, which may soon be within reach. Were just at the cusp of being able to write genomes, said Chris Organ, an evolutionary biologist at Montana State University. Well be able to actually manipulate genome size in the lab and study its effects. Those results may help to disentangle the features of genomes that are purely products of chance from those with functional significance.

Many experts would also like to see more analyses like Kapustas. (Lets do the same thing in insects! Johnston said.) As more genomes come online, researchers can begin to compare larger numbers of lineages. Four to five years from now, every mammal will be sequenced, Lynch said, and well be able to see whats happening on a finer scale. Do genomes undergo rapid expansion followed by prolonged contraction as populations spread, as Lynch suspects? Or do changes happen smoothly, untouched by population dynamics, as Petrovs and Feschottes models predict and recent work in flies supports?

Or perhaps genomes are unpredictable in the same way life is unpredictable with exceptions to every rule. Biological systems are like Rube Goldberg machines, said Jeff Bennetzen, a plant geneticist at the University of Georgia. If something works, it will be done, but it can be done in the most absurd, complicated, multistep way. This creates novelty. It also creates the potential for that novelty to change in a million different ways.

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Shrinking Bat DNA and Elastic Genomes - Quanta Magazine

Rare mutations in the amyloid precursor protein (APP) have previously been shown to be strongly associated with Alzheimer's disease (AD). Common genetic variants in this protein may also be linked to intelligence (IQ) in children, according to recent research performed at the University of Bergen, Norway.

Results of the research were published online today in the Journal of Alzheimer's Disease. Senior author Dr. Tetyana Zayats is a researcher at the KGJebsen Centre for Neuropsychiatric Disorders at the University of Bergen.

The study analyzed genetic markers and IQ collected from 5,165 children in the Avon Longitudinal Study of Parents and Children. The genetic findings were followed up in the genetic data from two adult datasets (1) 17,008 cases with AD and 37,154 controls, and (2) 112,151 individuals assessed for general cognitive functioning. The function of the genetic markers was analysed using reporter assays in cells.

Brain cells communicate via synapses containing hundreds of specialized proteins. Mutations in some of these proteins lead to dysfunctional synapses and brain diseases such as epilepsy, intellectual disability, autism or AD. Dr. Zayats and co-workers at the University of Bergen examined a subgroup of these proteins that have been implicated in synaptic plasticity and learning (the ARC complex). They found that a variation in DNA sequence within the gene encoding a member of this group of proteins, amyloid beta precursor protein (APP) was associated with non-verbal (fluid) intelligence in children, which reflects our capacity to reason and solve problems. In adults, this variation revealed association with AD, while the overall genetic variation within the APP gene itself appeared to be correlated with the efficiency of information processing (reaction time).

"This study has potential implications for our understanding of the normal function of these synaptic proteins as well as their involvement in disease" said Dr. Zayats.

APP encodes the amyloid- precursor protein that forms amyloid--containing neuritic plaques, the accumulation of which is one of the key pathological hallmarks in AD brains. However, it is unclear how these plaques affect brain functions and whether they lead to AD.

"Our understanding of biological processes underlying synaptic functioning could be expanded by examining human genetics throughout the lifespan as genetic influences may be the driving force behind the stability of our cognitive functioning," Dr. Zayats commented.

Genetic correlation between intelligence and AD has also been found in large-scale genome-wide analyses on general cognitive ability in adults. Several genes involved in general intelligence have previously reported to be associated with AD or related dementias. Such overlap has also been noted for the APP gene, where a coding variant was shown to be protective against both AD and cognitive decline in elderly.

"While this is only an exploratory study, in-depth functional and association follow up examinations are needed," Dr. Zayats noted. "Examining genetic overlap between cognitive functioning and AD in children - not only adults - presents us with a new avenue to further our understanding of the role of synaptic plasticity in cognitive functioning and disease."

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A protein involved in Alzheimer's disease may also be implicated in cognitive abilities in children - Medical Xpress

Scientists in Portland, Ore., just succeeded in creating the first genetically modified human embryo in the United States, according toTechnology Review. Ateam led by Shoukhrat Mitalipov ofOregon Health & Science Universityis reported to have broken new ground both in the number of embryos experimented upon and by demonstrating that it is possible to safely and efficiently correct defective genes that cause inherited diseases.

The U.S. teamsresults follow two trialsone last year and one in Aprilby researchers in Chinawho injected genetically modified cells into cancer patients.Theresearch teamsused CRISPR, a new gene-editing system derived from bacteria thatenables scientists to editthe DNA of living organisms.

The era of human gene editing has begun.

In the short term, scientists are planning clinical trials to use CRISPR to edit human genes linked to cystic fibrosis and other fatal hereditary conditions. But supporters of synthetic biology talk up huge potential long-term benefits. We could, they claim, potentially edit genes and build new ones to eradicate all hereditary diseases. With genetic alterations, we might be able to withstand anthrax attacks or epidemics of pneumonic plague. We might revive extinct species such as the woolly mammoth. We might design plants that are far more nutritious, hardy, and delicious than what we have now.

But developments in gene editing are alsohighlighting a desperate need for ethical and legal guidelines to regulate in vitro genetic editingand raising concerns about a future in which the well-off couldpay for CRISPR to perfect their offspring. We will soon be faced with very difficult decisions aboutwhen and how to use this breakthrough medical technology.For example, if your unborn child were going to have a debilitating disease that you could fix by taking a pill to edit theirgenome, would you take the pill? How about adding some bonusintelligence? Greater height or strength? Where would you draw the line?

CRISPRs potential for misuse by changinginherited human traits has prompted some genetic researchersto call fora global moratoriumon usingthe techniqueto modify human embryos. Such use is a criminal offense in 29 countries, and the United States bans the use of federal funds to modify embryos.

Still, CRISPRs seductiveness is beginning to overtake the calls forcaution.

In February, an advisory body fromthe National Academy of Sciences announcedthe academys support for usingCRISPR to edit the genes of embryos to remove DNA sequences that doctors saycause serious heritable diseases. The recommendation came with significant caveats and suggested limiting the use of CRISPR to specific embryonic problems. That said, the recommendation is clearly an endorsement of CRISPR as a research tool that is likely to become a clinical treatmenta step from which therewill be no turning back.

CRISPRs combination of usability, low cost, and power is both tantalizing and frightening, with the potential tosomeday enableanyone to edit a living creature on the cheap in their basements. So, although scientists might use CRISPR to eradicate malaria by making the mosquitoes that carry it infertile, bioterrorists could use it to create horrific pathogens that could kill tens of millions of people.

With the source code of life now so easy to hack, and biologists and the medical world ready to embrace its possibilities, how do we ensure the responsible use of CRISPR?

Theres a line that A Prairie Home Companion host Garrison Keillor uses whendescribing the fictional town of Lake Wobegon, whereall the children are above average. Will we enter a time when those who can afford a better genome will live far longer, healthier lives than those who cannot? Should the U.S. government subsidize genetic improvements to ensure a level playing field when the rich have access to the best genetics that money can buy and the rest of society does not? And what if CRISPR introduces traits into the human germ line with unforeseen consequencesperhaps higher rates of cardiac arrest or schizophrenia?

Barriers to mass use of CRISPR are already falling.Dog breeders looking to improve breedssuffering from debilitating maladies are actively pursuing gene hacking. A former NASA fellow in synthetic biology now sells functional bacterial engineering CRISPR kits for $150 from his online store. Its not hard to imagine a future in which the big drugstore chains carry CRISPR kits for home testing and genetic engineering.

The release ofgenetically modified organismsinto the wildin the past few years has raised considerable ethical and scientific questions. The potential consequences of releasing genetically crippled mosquitoes in the southern United States to reduce transmission of tropical viruses, for instance, drew a firestorm of concern over the effects on humans and the environment.

So, while the prospect of altering the genes of peoplemodern-day eugenicshas caused a schism in the science community, research with precisely that aim is happening all over the world.

We have arrived at a Rubicon. Humans are on the verge of finally being able to modify their own evolution. The question is whether they can use this newfound superpower in a responsible way that will benefit theplanet and its people. And a decision so momentous cannot be left to the doctors, the experts, orthe bureaucrats.

Failing to figure out how to ensure that everyonewill benefit from this breakthroughrisks the creation of a genetic underclasswho must struggle to compete with the genetically modified offspring of the rich. Andfailing to monitor and contain how we use itmay spell global catastrophe. Its up to us collectively to get this right.

This article was originally published byThe Washington Post. Read theoriginal article.

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The Era of Human Gene Editing Is HereWhat Happens Next Is Critical - Singularity Hub

For the first time in the United States, scientists have edited the genes of human embryos, a controversial step toward someday helping babies avoid inherited diseases.

The experiment was just an exercise in science the embryos were not allowed to develop for more than a few days and were never intended to be implanted into a womb, according to MIT Technology Review, which first reported the news.

Officials at Oregon Health & Science University confirmed Thursday that the work took place there and said results would be published in a journal soon. It is thought to be the first such work in the U.S.; previous experiments like this have been reported from China. How many embryos were created and edited in the experiments has not been revealed.

The Oregon scientists reportedly used a technique called CRISPR, which allows specific sections of DNA to be altered or replaced. It's like using a molecular scissors to cut and paste DNA, and is much more precise than some types of gene therapy that cannot ensure that desired changes will take place exactly where and as intended. With gene editing, these so-called "germline" changes are permanent and would be passed down to any offspring.

The approach holds great potential to avoid many genetic diseases, but has raised fears of "designer babies" if done for less lofty reasons, such as producing desirable traits.

Last year, Britain said some of its scientists could edit embryo genes to better understand human development.

And earlier this year in the U.S., the National Academy of Sciences and National Academy of Medicine said in a report that altering the genes of embryos might be OK if done under strict criteria and aimed at preventing serious disease.

"This is the kind of research that the report discussed," University of Wisconsin-Madison bioethicist R. Alta Charo said of the news of Oregon's work. She co-led the National Academies panel but was not commenting on its behalf Thursday.

"This was purely laboratory-based work that is incredibly valuable for helping us understand how one might make these germline changes in a way that is precise and safe. But it's only a first step," she said.

"We still have regulatory barriers in the United States to ever trying this to achieve a pregnancy. The public has plenty of time" to weigh in on whether that should occur, she said. "Any such experiment aimed at a pregnancy would need FDA approval, and the agency is currently not allowed to even consider such a request" because of limits set by Congress.

One prominent genetics expert, Dr. Eric Topol, director of the Scripps Translational Science Institute in La Jolla, Calif., said gene editing of embryos is "an unstoppable, inevitable science, and this is more proof it can be done."

Experiments are in the works now in the U.S. using gene-edited cells to try to treat people with various diseases, but "in order to really have a cure, you want to get this at the embryo stage," he said. "If it isn't done in this country, it will be done elsewhere."

There are other ways that some parents who know they carry a problem gene can avoid passing it to their children, he added. They can create embryos through in vitro fertilization, screen them in the lab and implant only ones free of the defect.

Dr. Robert C. Green, a medical geneticist at Harvard Medical School, said the prospect of editing embryos to avoid disease "is inevitable and exciting," and that "with proper controls in place, it's going to lead to huge advances in human health."

The need for it is clear, he added: "Our research has suggested that there are far more disease-associated mutations in the general public than was previously suspected."

Hank Greely, director of Stanford University's Center for Law and the Biosciences, called CRISPR "the most exciting thing I've seen in biology in the 25 years I've been watching it," with tremendous possibilities to aid human health.

"Everybody should calm down" because this is just one of many steps advancing the science, and there are regulatory safeguards already in place. "We've got time to do it carefully," he said.

Michael Watson, executive director of the American College of Medical Genetics and Genomics, said the college thinks that any work aimed at pregnancy is premature, but the lab work is a necessary first step.

"That's the only way we're going to learn" if it's safe or feasible, he said.

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In US first, scientists edit genes of human embryos - Indiana Gazette

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.

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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.

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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.

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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.

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human genetics | biology | Britannica.com