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Did Neanderthal genes raise modern's type 2 diabetes and Crohn's disease risk?

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Neanderthals' genetic legacy: type 2 diabetes in modern peoples? Remnants of Neanderthal DNA in modern humans are associated with genes affecting type 2 diabetes, Crohn's disease, lupus, biliary cirrhosis and smoking behavior, says a January 29, 2014 news release by by Stephanie Dutchen, "Neanderthals' genetic legacy." They also concentrate in genes that influence skin and hair characteristics. At the same time, Neanderthal DNA is conspicuously low in regions of the X chromosome and testes-specific genes.

The research, led by Harvard Medical School geneticists and published Jan. 29, 2014 in Nature, suggests ways in which genetic material inherited from Neanderthals has proven both adaptive and maladaptive for modern humans. You can check out the abstract of the study, "The genomic landscape of Neanderthal ancestry in present-day humans," published January 29, 2014 in Nature. (A related paper by a separate team also was published concurrently, January 29, 2014 in Science.)

"Now that we can estimate the probability that a particular genetic variant arose from Neanderthals, we can begin to understand how that inherited DNA affects us," says David Reich, according to the news release. Reich is a professor of genetics at HMS and senior author of the paper. "We may also learn more about what Neanderthals themselves were like."

What percentage of modern Europeans and Asians contain Neanderthal DNA?

In the past few years, studies by groups including Reich's have revealed that present-day people of non-African ancestry trace an average of about 2 percent of their genomes to Neanderthals—a legacy of interbreeding between humans and Neanderthals that the team previously showed occurred between 40,000 to 80,000 years ago. (Indigenous Africans have little or no Neanderthal DNA because their ancestors did not breed with Neanderthals, who lived in Europe and Asia.)

Several teams have since been able to flag Neanderthal DNA at certain locations in the non-African human genome, but until now, there was no survey of Neanderthal ancestry across the genome and little understanding of the biological significance of that genetic heritage.

"The story of early human evolution is captivating in itself, yet it also has far-reaching implications for understanding the organization of the modern human genome," explains Irene A. Eckstrand of the National Institutes of Health's National Institute of General Medical Sciences, which partially funded the research. "Every piece of this story that we uncover tells us more about our ancestors' genetic contributions to modern human health and disease."

Deserts and Oases

Reich and colleagues—including Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Germany—analyzed genetic variants in 846 people of non-African heritage, 176 people from sub-Saharan Africa, and a 50,000-year-old Neanderthal whose high-quality genome sequence the team published in 2013.

The most powerful information the researchers used to determine whether a gene variant came from a Neanderthal was if the variant appeared in some non-Africans and the Neanderthal but not in the sub-Saharan Africans

Using this and other types of information, the team found that some areas of the modern non-African human genome were rich in Neanderthal DNA, which may have been helpful for human survival, while other areas were more like "deserts" with far less Neanderthal ancestry than average.

The barren areas were the "most exciting" finding, says first author Sriram Sankararaman of HMS and the Broad Institute, according to the news release. "It suggests the introduction of some of these Neanderthal mutations was harmful to the ancestors of non-Africans and that these mutations were later removed by the action of natural selection."

Harmful mutations were removed by natural selection

The team showed that the areas with reduced Neanderthal ancestry tend to cluster in two parts of our genomes: genes that are most active in the male germline (the testes) and genes on the X chromosome. This pattern has been linked in many animals to a phenomenon known as hybrid infertility, where the offspring of a male from one subspecies and a female from another have low or no fertility.

"This suggests that when ancient humans met and mixed with Neanderthals, the two species were at the edge of biological incompatibility," says Reich, according to the news release. Reich also is a senior associate member of the Broad Institute and an investigator at the Howard Hughes Medical Institute.

Present-day human populations, which can be separated from one another by as much as 100,000 years (such as West Africans and Europeans), are fully compatible with no evidence of increased male infertility. In contrast, ancient human and Neanderthal populations apparently faced interbreeding challenges after 500,000 years of evolutionary separation. "It is fascinating that these types of problems could arise over that short a time scale," Reich says in the news release.

A Lasting Heritage

The team also measured how Neanderthal DNA present in human genomes today affects keratin production and disease risk. Neanderthal ancestry is increased in genes affecting keratin filaments. This fibrous protein lends toughness to skin, hair and nails and can be beneficial in colder environments by providing thicker insulation, said Reich. "It's tempting to think that Neanderthals were already adapted to the non-African environment and provided this genetic benefit to humans," he speculates.

The researchers also showed that nine previously identified human genetic variants known to be associated with specific traits likely came from Neanderthals. These variants affect diseases related to immune function and also some behaviors, such as the ability to stop smoking. The team expects that more variants will be found to have Neanderthal origins.

The team has already begun trying to improve their human genome ancestry results by analyzing multiple Neanderthals instead of one

Together with colleagues in Britain, they also have developed a test that can detect most of the approximately 100,000 mutations of Neanderthal origin they discovered in people of European ancestry. They are conducting an analysis in a biobank containing genetic data from half a million Britons.

"I expect that this study will result in a better and more systematic understanding of how Neanderthal ancestry affects variation in human traits today," says Sankararaman in the news release.

As another next step, the team is studying genome sequences from people from Papua New Guinea to build a database of genetic variants that can be compared to those of Denisovans, a third population of ancient humans that left most of its genetic traces in Oceania but little in mainland Eurasia.

This research was supported by the Presidential Innovation Fund of the Max Planck Society, NSF HOMINID grant 1032255, NIH grant GM100233 and the Howard Hughes Medical Institute.

A substantial fraction of the Neanderthal genome persists in modern human populations

Now a new approach applied to analyzing whole-genome sequencing data from 665 people from Europe and East Asia shows that more than 20 percent of the Neanderthal genome survives in the DNA of this contemporary group, whose genetic information is part of the 1,000 Genomes Project. Previous research proposes that someone of non-African descent may have inherited approximately 1 percent to 3 percent of his or her genome from Neanderthal ancestors.

Neanderthal lineages were excavated from modern human genomes in a new study using a fossil-free method of sequencing archaic DNA. The latest research may provide insight into human evolution. The new study, "Resurrecting Surviving Neanderthal Lineages from Modern Human Genomes: Shadows in Us," is published today, January 29, 2014 in Science. You can check out the study's abstract online.

Which Neanderthal sequences did we inherit?

Significant amounts of population-level DNA sequences might be obtained from extinct groups even in the absence of fossilized remains, because these archaic sequences might have been inherited by other individuals from whom scientists can gather genomic data.

These archaic DNA sequences can vary from one person to another and were aggregated in the present study to determine the extent of the Neanderthal genome remaining in the study group as a whole. The findings are a start to identifying the location of specific pieces of Neanderthal DNA in modern humans and a beginning to creating a collection of Neanderthal lineages surviving in present-day human populations.

University of Washington scientists Benjamin Bernot and Joshua M. Akey, both population geneticists from the Department of Genome Sciences, report their results Jan. 29 in Science Express. Vernot is a graduate student and Akey is an associate professor. Their paper is titled, "Resurrecting Surviving Neanderthal Lineages from Modern Human Genomes."

Scientists may no longer need a reference genome from an archaic species to do this type of study

To check the accuracy of their approach, Vernot ran their analysis before comparing the suspected Neanderthal sequences they found in modern humans to the recently mapped Neanderthal genome obtained from DNA recovered from bone. This genome came from the paleogenetics laboratory of Svante Paabo of the Max Planck Institute for Evolutionary Anthropology in Germany.

"We wanted to know how well our predictions matched the Neanderthal reference genome," Akey says, according to the January 29, 2014 news release, Neanderthal lineages excavated from modern human genomes. "The analysis showed that, after more refinement of these methods, scientists might not need a reference genome from an archaic species to do this type of study."

A lot of DNA sequences might be obtained from extinct groups without the need to examine fossils

The results suggest that significant amounts of population-level DNA sequences might be obtained from extinct groups even in the absence of fossilized remains, because these ancient sequences might have been inherited by other individuals from whom scientists can gather genomic data, according to Akey. Therein lies the potential to discover and characterize previously unknown archaic humans that bred with early humans. "In the future, I think scientists will be able to identify DNA from other extinct hominin, just by analyzing modern human genomes," Vernot explains in the news release.

"From our end, this was an entirely computational project," he adds, in the news release. "I think it's really interesting how careful application of the correct statistical and computational tools can uncover important aspects of health, biology and human history. Of course, you need good data, too."

Neanderthals became extinct about 30,000 years ago. Their time on the earth, and some of their geographic range, overlapped with humans who anatomically resembled us

The two closely related groups mated and produced some fertile offspring, such that portions of Neanderthal DNA were passed along to the next generations. In a proposed model, this mixing of DNA could have occurred both before and after the evolutionary divergence of non-African modern humans from a common ancestral population.

It didn't necessarily take a lot of individual hybrid offspring to introduce Neanderthal genes into early human populations

Still, Akey says that it isn't known how many Neanderthal ancestors present-day humans have. But past interactions between the groups, Akey notes, is probably more complicated than previously thought.

"In addition, the analysis of surviving archaic lineages points to the possibility that there were fitness costs to the hybridization of Neanderthal and humans," Akey says in the news release. "I think what was most surprising to me," Vernot notes, "is that we found evidence of selection. Last year, I would have bet that a Neanderthal/human hybrid would have been as fit as a fully modern human. This was mostly because we haven't been separated from them that long, on an evolutionary scale."

Nevertheless, the Neanderthals were also a probable source for at least a few genetic variations that were adaptive for their human descendants

Neanderthal DNA sequences are found in regions of the genome that have been linked to the regulation of skin pigmentation. The acquisition of these variants by mating with the Neanderthals may have proven to be a rapid way for humans to adapt to local conditions.

"We found evidence that Neanderthal skin genes made Europeans and East Asians more evolutionarily fit," Vernot says in the news release, "and that other Neanderthal genes were apparently incompatible with the rest of the modern human genome, and thus did not survive to present day human populations."

The researchers observed that certain chromosomes arms in humans are tellingly devoid of Neanderthal DNA sequences, perhaps due to mismatches between the two species along certain portions of their genetic materials. For example, they noticed a strong depletion of Neanderthal DNA in a region of human genomes that contains a gene for a factor thought to play an important role in human speech and language.

Fossil-free method of sequencing ancient, prehistoric genes

According to the scientists, the "fossil free" method of sequencing archaic genomes not only holds promise in revealing aspects of the evolution of now-extinct archaic humans and their characteristic population genetics, it also might provide insights into how interbreeding influenced current patterns of human diversity. Additionally, such studies might also help researchers hone in on genetic changes not found in any other species, and learn if these changes helped endow early people with uniquely human attributes.

In the photo from Clare McLean/University of Washington that you see next to this article, are University of Washington population geneticists Joshua Akey (left) and Benjamin Vernot (right) discussing models of human evolution. Akey is an associate professor, and Vernot is a graduate student, both in the University of Washington Department of Genome Sciences.

When populations collide: The genomic landscape of Neanderthal ancestry in present-day humans

More than thirty thousand years ago, Homo sapiens migrating out of Africa began encountering Neanderthals, a lineage that had diverged from modern humans hundreds of thousands of years before. Despite their differences, Homo sapiens and Neanderthals mingled, and over time, produced children with genes from both lineages. Today, the biological remnants of that collision between two distinct populations remain alive in the genomes of humans with European and Asian ancestry, according to the January 29, 2014 news release, "When populations collide."

Now, Howard Hughes Medical Institute (HHMI) researchers at Harvard Medical School have analyzed exactly which areas of the human genome retain segments of Neanderthal DNA, passed down throughout the generations. The findings were published January 29, 2014 in Nature.

"The goal was to understand the biological impact of the gene flow between Neanderthals and modern humans," says David Reich, in the January 29, 2014 news release, "When populations collide." Reich is an HHMI investigator at Harvard Medical School and the lead scientist on the new research. "We reasoned that when these two groups met and mixed, some new traits would have been selected for and remained in the human genome, while some incompatibilities would have been selected against and removed."

Reich is interested in the research area of what happens when populations collide

"Throughout history, groups of humans have been on the move. Until recently, researchers did not have the ability to learn much about what happened when two populations met each other, and in particular whether they mixed or one replaced the other," Reich says in the news release. What really happens, he argues, is that populations mix, and that later people carry DNA from both ancestral groups.

In late 2013, Reich was one of the leaders of a team that published the complete genome of a Neanderthal woman, based on analysis of DNA isolated from a toe bone discovered in modern-day Siberia. To determine how the human-Neanderthal genetic mixing may have played out, Reich and his colleagues compared that completed Neanderthal genome with the genomes of 1,004 present-day humans from around the globe.

Genome of some Neanderthals compared to some present day humans from around the world

"If a gene variant is absent in Africans today, but present in modern day non-Africans as well as the Neanderthal genome, that's good evidence that it originates from Neanderthals," Reich says. Since humans met Neanderthals as they migrated out of Africa, those populations that remained in Africa had little contact or genetic mixing with Neanderthals. Reich's group also leveraged other genetic information, including the size of different gene fragments, to determine whether genes were inherited from Neanderthals or not.

The researchers found that today, humans in east Asia have, on average, more of their genome originating from Neanderthals than Europeans, and modern-day Africans have little or none. Those findings confirmed previous studies. But then, the scientists took their analysis a step further and examined which genes most often have Neanderthal ancestry in present-day people. They found that some genes had variants of Neanderthal origin in more than sixty percent of Europeans or Asians, while other genes were never of Neanderthal heritage.

The scientists discovered that the genetic changes most often inherited from Neanderthals were disproportionately in genes related to keratin, a component of skin and hair

"This suggests that as humans were adapting to the non-African environment they were moving into, they may have been able to exploit adaptations that Neanderthals had already achieved," Reich says in the news release. More work is needed, however, to show the exact biological implications of the Neanderthal keratin genes and how they differ from the versions of keratin related proteins that would have already been present in modern humans.

His group analyzed not only which Neanderthal genes remain in the human population today, but also which parts of today's genomes lack Neanderthal genes altogether. "The most interesting findings were about the places in the genome that are devoid of Neanderthal genes – 'Neanderthal ancestry deserts'," says Reich. "At these locations, Neanderthal genetic material was not tolerated by modern humans and removed by the action of natural selection."

The new study revealed that genetic changes that affect risk for lupus, diabetes, and Crohn's Disease likely originate from Neanderthals

The most striking area of the human genome that lacked Neanderthal genes was the X chromosome—one of the sex chromosomes. In humans, women have two X chromosomes and men have an X and a Y chromosome. The team's observation that the X chromosome had very little Neanderthal ancestry suggested something the scientists hadn't predicted -- a biological phenomenon called hybrid sterility.

When two organisms are distantly related, Reich explains, genes related to fertility, inherited on the X chromosome, can interact poorly with genes elsewhere in the genome

The interference between the pairs of genes can render males—who only have one X chromosome—infertile. "When you have populations that have sufficiently diverged, this male-only sterility can occur," Reich says in the news release. To confirm whether hybrid sterility could have occurred during the interbreeding between modern humans and Neanderthals, Reich's team looked at whether genes expressed in the testes were more or less enriched in Neanderthal DNA.

Indeed, genes important for the functioning of the testes had a particularly low inheritance of Neanderthal ancestry. The combined evidence that both the testes and the X chromosome lack Neanderthal DNA, Reich says, suggests that modern human males who inherited a Neanderthal X chromosome often may have been unable to have children, and therefore pass along this X chromosome. Today, that translates into a near- absence of Neanderthal DNA on the X chromosomes of humans.

"It tells us that when Neanderthals and modern humans met and mixed, they were at the very edge of being biological compatible," he says in the news release.

Further studies on the legacy of Neanderthal genes in human biology could help shed light on not only human history, but the overall biological idea of hybrid sterility. "The other direction we want to go is to use this information as a tool for understanding human disease genes," Reich adds, according to the news release.

Already, the new study revealed that genetic changes that affect risk for lupus, diabetes, and Crohn's Disease likely originate from Neanderthals. More news about Neanderthal-human genetic studies of interest include, "Sunlight adaptation region of Neanderthal genome found in up to 65 percent of modern East Asian Population" and "Neanderthal genome shows early human interbreeding, inbreeding."

You also may wish to see the abstracts of these Neanderthal or Denisovan-related studies in Nature: The complete genome sequence of a Neanderthal from the Altai Mountains, December 18, 2013, Genetic history of an archaic hominin group from Denisova Cave in Siberia, December 22, 2010, and Analysis of one million base pairs of Neanderthal DNA, November 16, 2006.

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