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Ancient European Genome Studies Reveal Historical Population Interactions, Modern-Day Disease Clues

NEW YORK – In a new research collection, members of an international team outline efforts to characterize ancient population patterns in northwestern Eurasia with the help of a gene bank encompassing thousands of ancient genomes, established by the University of Copenhagen's Lundbeck Foundation GeoGenetics Centre in collaboration with universities and museums across Europe.

"There's no doubt that an ancient genomic dataset of this size will have applications in many different contexts within disease research," project director Eske Willerslev, a researcher affiliated with the University of Cambridge, University of Copenhagen, and St. John's College, said in a statement.

"As new scientific discoveries derived from the 5,000-genome dataset become published, more data will gradually be made freely available to all researchers," Willerslev explained. "Ultimately, the complete dataset will be open access for everyone."

For a paper published in Nature on Wednesday, researchers from the University of Copenhagen, the University of Cambridge, and other international centers performed shotgun sequencing on 317 ancient samples from northern and western Eurasia, focusing on samples from the Mesolithic and Neolithic periods.

"Our sampling was particularly dense in Denmark," the authors explained. "Dense sampling was also obtained from Ukraine, western Russia, and the trans-Ural region, spanning the Early Mesolithic through to the Neolithic, up to around 5,000 [years before present]."

After bringing in imputed genome sequence data for another 1,664 ancient samples profiled in past studies, the team was able to start untangling genetic similarities and differences within and between populations in the region, along with genetic distinctions found in northern and western Eurasia today.

Among other population patterns, the investigators described genetic distinctions between populations on the east and west sides of the region, potentially due to distinct climate conditions in each region. While the west portion of the region was marked by a Neolithic transition to farming, for example, a similar expansion was not found in the eastern region for another 3,000 or so years.

Instead, the team saw signs of a complex Mesolithic hunter-gatherer culture that continued for thousands of years longer in the east, until a more recent population turnover reflecting the arrival of livestock-herding Yamnaya steppe pastoralists with their own hunter-gatherer ancestry from the Pontic-Caspian steppe region.

"We have provided evidence for the existence of clear east-west genetic division extending from the Black Sea to the Baltic, mirroring archaeological observations, and persisting for several millennia," they wrote. "We show that this deep ancestry division in the Eurasian human gene pool that was established during early [post-Last Glacial Maximum] dispersals was maintained throughout the Mesolithic and Neolithic ages."

In another Nature study, investigators at the University of Copenhagen, University of Cambridge, and other international centers shared findings from a natural selection-centered analysis that included genome sequences for 1,664 skeletal samples from archeological sites in Middle Stone Age Eurasia reaching back more than 3,000 years that were assessed by sequencing and imputation for the current analysis and published studies.

Together with modern-day European genetic profiles for some 400,000 UK Biobank participants, the team's data highlighted signs of selection in the ancient populations that are suspected of impacting everything from body height or bipolar disorder risk to tolerance for vegetables and lactose sugar in dairy products.

In particular, the investigators unearthed diabetes and Alzheimer's disease-related variants going back to Western hunter-gatherer groups, along with steppe ancestry-associated variants linked to height increases described in northern Europe compared to southern parts of the continent.

"It's striking that the lifestyles of the people in the Eurasian region over the last 10,000 years have resulted in a genetic legacy that impacts their present-day descendants, in terms of both their physical appearance and their risk of developing a number of diseases," co-first and co-corresponding author Evan Irving-Pease, a researcher with the University of Copenhagen's Lundbeck Foundation GeoGenetics Centre, said in a statement.

For their part, investigators at the University of Copenhagen, Curtin University, Gothenburg University, and elsewhere delved into 100 ancient genomes from Denmark, revealing two significant population turnovers going back to the Ice Age.

The first turnover involved a shift to a farming culture with the arrival of Anatolian migrants at the start of the Neolithic Age about 5,900 years ago, the team explained. A more recent turnover event saw the replacement of Anatolian farmers by Yamnaya livestock herders, who appeared to bring the ancient ancestors of present-day Danes about 5,000 years ago.

"Our analyses show that the hunter-gatherers virtually vanished within a few centuries in Denmark and the rest of Northwestern Europe," co-first author Martin Sikora, a population genetics researcher at the Lundbeck Foundation GeoGenetics Centre, said in a statement, noting that "Denmark experienced two population turnovers within just 1,000 years."

Finally, investigators at University of Cambridge, the University of Copenhagen, the University of Oxford, and elsewhere used bioinformatics, chromosome painting, and other population genetic approaches to assess available ancient sequences spanning the Mesolithic, Neolithic, Bronze Age, Iron Age, and Middle Ages, comparing autoimmune disease-related risk variant profiles to those found in UK Biobank participants.

With these approaches, the investigators tracked down risk variants previously implicated in the risk of multiple sclerosis (MS), a neurodegenerative and neuroinflammatory condition marked by autoimmune attacks on components of the central nervous system, in Yamnaya herders, suggesting migrants from this group carried MS risk variants from the Pontic Steppe in present-day Ukraine, southwest Russia, and Kazakhstan's West Kazakhstan Region to northern Europe some 5,000 years ago.

"This means we can now understand and seek to treat MS for what it actually is: the result of a genetic adaptation to certain environmental conditions that occurred back in our prehistory," University of Oxford Radcliffe Hospital researcher and consultant physician Lars Fugger, a co-senior and co-corresponding author on the study, said in a statement.

In particular, the researchers noted that MS- and rheumatoid arthritis-associated variants show apparent protective effects against some pathogens and infectious diseases, hinting that such risk variants may have helped Yamnaya herders dodge sheep- and cattle-borne infections.

"It must have been a distinct advantage for the Yamnaya people to carry the MS risk genes, even after arriving in Europe, despite the fact that these genes undeniably increased their risk of developing MS," co-senior and co-corresponding author Willerslev said in a statement, noting that the findings "change our view of the causes of multiple sclerosis and have implications for the way it is treated."

Together, the results offered insights into the overrepresentation of MS cases in populations from northern Europe compared with those found in southern Europe, while pointing to the possibility for better understanding other neurological or psychiatric conditions.

"We've demonstrated that our gene bank works as a precision tool that can give us new insights into human diseases, when combined with analyses of present-day human DNA data and inputs from several other research fields," Willerslev explained. "That, in itself, is amazing, and there's no doubt it has many applications beyond MS research."