Category Archives: Human Genetics

The Hindu

Too early to settle the Aryan migration debate? The Hindu Another study published in The American Journal of Human Genetics (2011; 89:731-744) by Mait Metspalu and colleagues, where CSIR-CCMB was also involved, analysed 142 samples from 30 ethnic groups and mentioned that Modeling of the observed ...

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Too early to settle the Aryan migration debate? - The Hindu

The American Society of Human Genetics (ASHG) has honored Dr. Arthur L. Beaudet, Henry and Emma Mayer Professor in the Department of Molecular and Human Genetics at Baylor College of Medicine, with the 2017 Victor A. McKusick Leadership Award.

This award, named in honor of the late Dr. Victor A. McKusick, recognizes individuals whose professional achievements have fostered and enriched the development of human genetics as well as its assimilation into the broader context of science, medicine and health.

It is an honor to accept the 2017 McKusick Award, said Beaudet, who also is a Professor in the Department of Pediatrics at Baylor and physician at Texas Childrens Hospital. The American Society of Human Genetics is a prominent organization for genetics specialists all over the world, and I am proud to join the ranks of past award winners, all of whom have contributed significantly to the field.

In the 1980s, Beaudet and colleagues were the first to document uniparental disomy, a phenomenon in which a person receives two copies of a chromosome from one parent and zero from the other. In the following years, they drew an important distinction between genetic and epigenetic diseases that both lead to altered expression of the same genes and identified ways to study these and better understand the conditions they caused. Currently, his research focuses on neuronal carnitine deficiency as a risk factor for autism; the role of genomic imprinting in diseases such as Prader-Willi syndrome, Angelman syndrome and autism; and prenatal genetic diagnosis based on fetal cells isolated from maternal blood.

In addition to his scientific leadership, ASHG also honors Beaudets contributions to the Society as well as the broader research community. A longtime member of ASHG, he belonged to its Program Committee from 1984-86, its Board of Directors from 1987-90, and its Awards Committee from 2010-12, and served as President in 1998. He received the Societys William Allan Award in 2007, and belonged to the Editorial Board of the ASHG-published The American Journal of Human Genetics from 1986-1989. In addition, he was awarded the Texas Genetics Society Barbara H. Bowman Award in 1999 and the March of Dimes Colonel Harland Sanders Award for Lifetime Achievement in Genetic Research and Education in 2002. He has published more than 350 articles in scientific literature.

Dr. Beaudets outstanding leadership in human genetics has transcended all aspects of the academic mission from clinical care, education and training, to basic and translational research, said Dr. Brendan Lee, the Robert and Janice McNair Endowed Chair and professor of molecular and human genetics, chair of the Department of Molecular and Human Genetics at Baylor and ASHG Executive Committee member.

ASHG will present the McKusick Award, which will include a plaque and $10,000 prize, to Beaudet on Tuesday, Oct. 17, during the organizations67th Annual Meetingin Orlando, Fla.

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Dr. Beaudet recognized for leadership in genetics - Baylor College of Medicine News (press release)

Scientists say the molar tooth found in Denisova Cave in Siberia estimate the tooth is at least 20,000 years older than previously examined Denisovan fossils.

DNA in a fossil from a young girl has revealed that a mysterious extinct human lineage occupied the middle of Asia longer than previously thought, allowing more potential interbreeding with Neanderthals, a new study finds.

Although modern humans are the only surviving human lineage, other hominins which include modern humans, extinct human species and their immediate ancestors once lived on Earth. These included Neanderthals, the closest extinct relatives of modern humans, as well as the Denisovans, who lived across a region that might have stretched from Siberia to Southeast Asia.

In 2010, researchers analyzed DNA from fossils to reveal the existence of the Denisovans, suggesting the lineage shared a common ancestor with Neanderthals. However, the Denisovans were nearly as genetically distinct from Neanderthals as Neanderthals were from modern humans, with the ancestors of Denisovans and Neanderthals splitting about 190,000 to 470,000 years ago. [Denisovan Gallery: Tracing the Genetics of Human Ancestors]

The 2010 study also revealed that the Denisovans might have interbred with modern humans thousands of years ago just as Neanderthalsdid. Subsequent research suggested that genetic mutations from Denisovanshave influenced modern human immune systems, as well as fat and blood sugar levels.

However, much remains unknown about the Denisovans, since all fossil evidence of them until now was limited to just three specimens: one finger bone and two molars. All three fossils were unearthed from Denisova Cave, after which the Denisovans are named, in the Altai Mountains in Siberia.

Now, scientists have revealed that they have a fourth Denisovan fossil a "baby tooth" that likely fell from the jaw of a 10- to 12-year-old girl, said study lead author Viviane Slon, a paleogeneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany.

"Any additional Denisovan individual that we can identify at this point is very exciting for us," Slon told Live Science.

The crown of the "baby" molar was almost completely worn away when researchers unearthed it. To help preserve the fossil, the researchers used 3D X-rays of the tooth to help find the best way to extract as little powder from the molar as possible. Next, they analyzed what little surviving DNA they could from about 10 milligrams of tooth powder, confirming that the fossil belonged to a Denisovan girl.

The deep layer of sediment in which this molar was found ranges from 128,000 to 227,000 years old. This age makes the tooth one of the oldest human specimens discovered in central Asia to date, and about 50,000 to 100,000 years older than the first known Denisovan fossil.

"This would indicate that Denisovans were present in the Altai area for a very long time at least as long as modern humans have been in Europe, if not much more," Slon said. Such a long span of time increases the chances that the Denisovans and the Neanderthals may have interacted and interbred, the researchers added.

These new findings, combined with previous data, suggest that there may have been low levels of genetic diversity among the Denisovans, comparable to the lower range of modern human genetic diversity seen among small or secluded populations.

"The low genetic diversity we infer for the Denisovans can most probably be linked to their small population size," Slon said. "This is similar to what has been inferred for Neanderthals. Both groups of archaic hominins seem to have had a far smaller population size than humans today."

Still, the researchers noted that because all four Denisovan fossils unearthed to date come from the same place, it is possible that they represent an isolated population and that Denisovan genetic diversity across

their entire geographic range was greater than that seen in these isolated samples. Additional fossils from Denisovans from other locations would help scientists more comprehensively gauge Denisovans' genetic diversity across space and time, Slon said.

The scientists detailed their findingsonline July 7 in the journal Science Advances.

Original article on Live Science.

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200,000-Year-Old Tooth Reveals Clues About Mysterious Human ... - Live Science

Its the ability of our immune system to remember past infections, and pass this memory on to our kids, that allows us to survive infectious diseases.

This is the second article in a four-part series looking at how infectious diseases have influenced our culture and evolution, and how we, in turn, have influenced them.

Its easy to feel our survival is under threat from new and emerging infectious diseases that are going to wipe out the human race, or at least end our current way of life. The recent outbreaks of Ebola in West Africa re-ignited our interest in pandemics and reminded us of our potential frailty in the face of an overwhelming enemy.

With so many microbes capable of hijacking and destroying us, how are we as a species still enduring?

Humans are unique in the world. We are avid collectors of infectious diseases acquired from our environment throughout our evolution.

We share with our invaders a need to survive and propagate our genes. Infectious pathogens, such as bacteria and viruses, are parasitic they have to find and infect a susceptible host in order to maintain themselves and propagate. Therefore, its not really in their best interests to kill us. Our relationship with pathogens is shaped by our capacity to evolve genetically, to modify our behaviour, or to force the pathogens to evolve so that we all survive.

Viruses such as influenza replicate and spread to new hosts before the original host gets sick (with influenza symptoms such as a sore throat and sneezing), meaning the parasite can survive and thrive in new hosts.

On rare occasions the death of the host is necessary for the pathogen to reproduce. One example is trichinellosis (also known as trichinosis), which is caused by eating undercooked or raw meat from animals (usually carnivores and omnivores) infected with a worm (nematode).

To survive in the host the worm constructs a capsule around itself to avoid the immune system. The immature worms in the meat cause muscle weakness and paralysis, and eventually death, in the host. This means the victim is defenceless to predators that may come and gobble it up, thus giving the worm a new host to infect.

This is an old disease that we tackle either by avoiding eating meat (possibly the reason some religions avoid eating pork), or through cultural adaptation such as overcooking.

Evolutionary pressures through Darwinian selection, survival of the fittest, constantly shape life on Earth. This innate ability to adapt has enabled humans to develop defence mechanisms to counter some of the most devastating pathogens.

Malaria is a parasite of red blood cells that is estimated to have caused 429,000 deaths in 2015. When malaria became a human disease (it is thought to originate in primates) is unclear. One thing that is clear is that it emerged long enough ago for humans to evolve innate defences.

Sickle cell mutation is a potentially fatal blood disorder seen mainly in Africa. This mutation in a haemoglobin gene (responsible for red pigment in blood cells) is one of a number of genetic traits that actually protect against malaria. People who have this genetic mutation are protected against malaria and thus likely to reproduce and pass on their evolutionary advantage.

A second genetic mutation that protects humans against malaria affects an essential enzyme for red blood cell function. But individuals with this mutation may also develop life-threatening anaemia (deficiency in the number or quality of red blood cells) due to the destruction of red blood cells as a side effect of treatment with some modern anti-malarial drugs.

Perhaps the most significant and wondrous part of the evolutionary machinery that enables the human race to keep one step ahead of the pathogens is the major histocompatibility complex (MHC). The MHC proteins on the surface of our white blood cells evolved along with the vertebrates (animals with a spine), which makes them our oldest defence mechanism.

We have different types of white cells: mobile ones in the blood (lypmphocytes) and resident ones in lymph nodes (macrophages). When there is an infection the macrophages gobble up the bugs and present proteins from the organism on their surface like signals.

The lymphocytes containing MHC molecules that recognise this protein bind on. (Our immune system has memory cells that are produced after vaccination or past infections so we can remember how to fight them next time.) The lymphocytes then produce chemicals that recruit more lymphocytes to help. These multiply and you end up with a swollen gland.

Our bodys ability to remember past infections is one of the reasons the entire population of London didnt perish during the Black Death. MHC molecules are passed on to our offspring, which explains why we have such a wide variety of these molecules. When a disease enters a population for the first time it always more lethal than subsequent introductions because some people are now immune, and people have been born to the survivors.

Not all co-evolution leads to changes in human genetics, especially if there is no impact on our ability to procreate. Human tuberculosis is a chronic disease that continues to plague the world with little evidence that humans have developed any ability to resist infection. This is interesting because it is likely to have co-evolved with us from Neolithic times.

We will continue to face new and emerging diseases. So far our capacity to adapt and respond has served us well. But some scientists believe humans are no longer evolving due to the removal of many selection pressures, most importantly things that cause premature death.

The question is whether we are up to the challenges posed by what comes next. Perhaps the most pressing issue facing us now is that bugs seem to be evolving faster than we can create things to kill them known as anti-microbial resistance.

The spectre of life without antibiotics is terrifying given we never did overcome bacterial infections through evolution. Instead we used our ingenuity. Our future will reflect how well we exercise our collective intellect and will to dodge this bullet.

Read the first instalment in the series:

Four of the greatest infectious diseases of our time and how were overcoming them

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How we've evolved to fight the bugs that infect us - The Conversation AU

Mr. Lytle quickly denied that accusation and offered his own defense. They were going out eating every day but I was bringing my own lunch, trying to eat healthier, and reading a lot, he said. I guess I was just trying to make the best of the situation, because jury duty is usually never any fun.

But he found out otherwise on May 30, 2014 which happened to be his 27th birthday when he finally accepted one of those lunch offers, and went along with Ms. Nelson and two other jurors to a nearby restaurant/bar.

That day I learned that he has a very funny, subtle and surprising sense of humor, Ms. Nelson said. He notices small quirks in people.

He noticed a lot more than that in Ms. Nelson. She was very attractive and made me laugh, he said. She was also a very intelligent person who knew a lot about science and had a very interesting career.

They began going out for lunch with greater frequency, and one night in June, they went for drinks with four fellow jurors, all of whom disappeared during the course of the evening, leaving Ms. Nelson and Mr. Lytle alone in a social setting for the first time.

Ms. Nelson invited Mr. Lytle back to her apartment to watch an episode of The Bachelor, along with her roommate, and Mr. Lytle accepted. When the show ended, they went dancing at a Manhattan bar.

That was kind of the turning point in our relationship, said Ms. Nelson, who was living on the Upper East Side at the time, while Mr. Lytle lived in Washington Heights.

They were soon dating, and became a more serious item in the days after the trial ended in late July 2014.

The nicest thing about Jordan is that being with him always felt so natural and right, Ms. Nelson said. I met him at a time when I was going on a lot of first dates, and most of them always felt very childish, but Jordan was always kind and considerate and never one to play games. We just seem to balance each other out very well.

Recently, a friend of Ms. Nelsons called to bemoan the fact that she had received a jury duty notice.

It might not be as bad as you think, Ms. Nelson told her. You never know, you might meet your future husband there.

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Finding Love in a Lower Manhattan Courthouse - New York Times

July 6, 2017 Credit: CC0 Public Domain

Researchers have identified a rare genetic syndrome characterized by intellectual disability, seizures, an abnormal gait and distinctive facial features. The scientists pinpointed variants in the WDR26 gene as causes for this distinctive, yet unnamed condition. Their early research provides initial information for counseling patients and families coping with uncertainties for children with the rare, poorly recognized condition.

"Our study identifies 15 individuals now known to have this recognizable syndrome, but we expect that as this information reaches the medical community, more patients will be recognized," said study leader Matthew A. Deardorff, MD, PhD, a pediatric geneticist at Children's Hospital of Philadelphia (CHOP). "Our studies are very much in the early stage, but as we continue to gain more clinical and scientific knowledge about this condition, we will be able to better explain to parents what to expect."

Deardorff, first author Cara M. Skraban, MD, also of CHOP, and co-authors from medical centers in six countries published their research today in the American Journal of Human Genetics.

"Prior to our identification of individuals with changes in this gene, it was not even listed in some of the most commonly used databases," said Deardorff. "The notable efforts by our colleagues here in the Division of Genomic Diagnostics at CHOP, and at key labs in the Netherlands and Maryland, helped us to make this discovery possible."

The scientists reported on 15 individuals, ranging from two years old to 34 years old. All the patients had developmental delays (ranging from mild to severe), seizures, and similar facial features (such as wide mouths, prominent upper lip and gums, full cheeks and a broad nasal tip). Many had subtle abnormalities in their gait. All 15 had de novo (new) mutationsthose arising in a single egg or sperm that developed into the affected patient, but did not occur in the patient's parents.

The group at CHOP, along with global collaborators, is working energetically to understand the syndrome's functional details and underlying mechanisms. Although the specifics are still under investigation, the authors suggest that haploinsufficiency (reduced expression) of the WDR26 gene alters multiple signaling pathways and cell functions to produce features of the syndrome.

"There is no good laboratory assay yet for the effects of these mutations, but clinicians may notice facial differences or other signs, and would typically order exome sequencing, which would diagnose this syndrome," said Deardorff. "If testing confirms this diagnosis, we advise parents that seizures may occur, which are usually treatable with standard medicines. It may be possible that early intervention with special education can help address a child's intellectual disability, although we do not yet have enough clinical data to develop full guidelines for medical management."

Deardorff added that CHOP has started a patient registry to compile clinical data on this rare condition, and that this data collection may offer a resource for families interested in contacting each other to share information and support. He added, "This discovery is just the first step in understanding why changes in WDR26 cause intellectual disability and seizures. With further investigation, our goal is to better understand the biology and identify specific treatments for these children."

Explore further: New genetic syndrome tied to defects in protein transport

More information: Cara M. Skraban et al, "WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features," American Journal of Human Genetics, published July 6, 2017 doi.org/10.1016/j.ajhg.2017.06.002

An international team of researchers has discovered the mutation responsible for a rare, newly identified genetic disorder that causes craniofacial abnormalities and developmental delays. The mutation disrupts normal protein ...

Pediatric researchers, using high-speed DNA sequencing tools, have identified a new syndrome that causes intellectual disability (ID). Drawing on knowledge of the causative gene mutation, the scientists' cell studies suggest ...

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New genetic syndrome identified; may offer some answers for puzzled parents - Medical Xpress

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

This story wasoriginally publishedonSpectrum.

Originally posted here:
Using Big Data to Hack Autism - Scientific American

How did our distinctive brains evolve? What genetic changes, coupled with natural selection, gave us language? What allowed modern humans to form complex societies, pursue science, create art?

While we have some understanding of the genes that differentiate us from other primates, that knowledge cannot fully explain human brain evolution. But with a $10 million grant to some of Bostons most highly evolved minds in genetics, genomics, neuroscience and human evolution, some answers may emerge in the coming years.

The Seattle-based Paul G. Allen Frontiers Group has announced the creation of an Allen Discovery Center for Human Brain Evolution at Boston Childrens Hospital and Harvard Medical School. It will be led by Christopher A. Walsh, the Bullard Professor of Pediatrics and Neurology at HMS and chief of the Division of Genetics and Genomics at Boston Childrens. Michael Greenberg, the Nathan Marsh Pusey Professor of Neurobiology and head of the Department of Neurobiology at HMS, and David Reich, professor of genetics at HMS, will co-lead the center.

Unraveling the mysteries of the human brain will propel our understanding of brain development, brain evolution and human behavior, said George Q. Daley, dean of HMS. It also will help us understand what makes us unique as a species.

The research conducted by these three remarkable scientists spans the gamut from molecule to organism to system and underscores the cross-pollination among basic, translational and clinical discovery as well as across neurobiology, genetics, evolutionary biology and neurology, Daley said.

The centers agenda is a bold one: to catalogue the key genes required for human brain evolution, to analyze their roles in human behavior and cognition and to study their functions to discover evolutionary mechanisms.

To understand when and how our modern brains evolved, we need to take a multi-pronged approach that will reflect how evolution works in nature and identify how experience and environment affect the genes that gave rise to modern human behavior, Walsh said.

The launch of this center is a wonderful opportunity for three laboratories that have been working independently to come together and study the genetic, molecular and evolutionary forces that have given rise to the spectacular capacities of the human brain, said Greenberg.

The funding will allow us to use ancient DNA analysis to track changes in the frequency of genetic mutations over time, which will in turn illuminate our understanding of the nature of human adaptation, added Reich.

An evolving understanding

We already know some basics of human brain evolution. First came the enlargement of the primate brain, culminating perhaps 2 million years ago with the emergence of our genus, Homo, and the use of crude stone tools and fire. Next came a tripling of brain size during the 500,000 years before Homo sapiens arose. Finally, just over 50,000 years ago, there was a great leap forward in human behavior, with archaeological evidence of more efficient manufacturing of stone tools and a rich aesthetic and spiritual life.

What transpired genetically? Prior research has taken a piecemeal approach to occasional genes that have different structures in humans versus non-humans. For example, Walshs lab has identified several genes that regulate cerebral cortical size and patterning, some of them through the study of brain abnormalities. The lab recently found a gene involved in brain foldingthanks to a brain malformation called polymicrogyriathat may have enhanced our language ability.

But such findings only scratch the surface of the cognitive, behavioral and cultural strides humans have made over the past 50,000 years. Thats a blink of the eye in evolutionary terms. What enabled us to invent money, develop agriculture, build factories, write symphonies, tell jokes?

Rosetta Stone(s) to decode brain evolution

The researchers think not one but multiple mechanisms of evolution helped form the modern human brain. Such mechanisms include:

Accordingly, the centers research methods will include, in varying combinations:

No genetic stone unturned

All these approaches will be supported by powerful computational data analysisreaching across genomes, across populations, across hundreds of thousands of years.

The project leaders summed it up: This group will provide the most rigorous possible examination of how, when and where the unique features of the amazing human brain came about.

The $10 million grant will be distributed over four years, with the potential for $30 million over eight years.

Adapted from a post on Vector, the Boston Childrens clinical and research innovation blog.

More:
Decoding Brain Evolution - Harvard Medical School (registration)

BBC News

6.8m genetic medicine plan for targeted treatment BBC News Patients in Wales will benefit from stronger services and more expertise in genetic medicine, under a new strategy. The 6.8m plan has been designed to ensure Wales is able to offer treatment plans revolutionised by better understanding of human DNA. and more »

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6.8m genetic medicine plan for targeted treatment - BBC News