The transitions from foraging to farming and later to pastoralism in Stone Age Eurasia (c. 11-3 thousand years before present, BP) represent some of the most dramatic lifestyle changes in human evolution. We sequenced 317 genomes of primarily Mesolithic and Neolithic individuals from across Eurasia combined with radiocarbon dates, stable isotope data, and pollen records. Genome imputation and co-analysis with previously published shotgun sequencing data resulted in >1600 complete ancient genome sequences offering fine-grained resolution into the Stone Age populations. We observe that: 1) Hunter-gatherer groups were more genetically diverse than previously known, and deeply divergent between western and eastern Eurasia. 2) We identify hitherto genetically undescribed hunter-gatherers from the Middle Don region that contributed ancestry to the later Yamnaya steppe pastoralists; 3) The genetic impact of the Neolithic transition was highly distinct, east and west of a boundary zone extending from the Black Sea to the Baltic. Large-scale shifts in genetic ancestry occurred to the west of this "Great Divide", including an almost complete replacement of hunter-gatherers in Denmark, while no substantial ancestry shifts took place during the same period to the east. This difference is also reflected in genetic relatedness within the populations, decreasing substantially in the west but not in the east where it remained high until c. 4,000 BP; 4) The second major genetic transformation around 5,000 BP happened at a much faster pace with Steppe-related ancestry reaching most parts of Europe within 1,000-years. Local Neolithic farmers admixed with incoming pastoralists in eastern, western, and southern Europe whereas Scandinavia experienced another near-complete population replacement. Similar dramatic turnover-patterns are evident in western Siberia; 5) Extensive regional differences in the ancestry components involved in these early events remain visible to this day, even within countries. Neolithic farmer ancestry is highest in southern and eastern England while Steppe-related ancestry is highest in the Celtic populations of Scotland, Wales, and Cornwall (this research has been conducted using the UK Biobank resource); 6) Shifts in diet, lifestyle and environment introduced new selection pressures involving at least 21 genomic regions. Most such variants were not universally selected across populations but were only advantageous in particular ancestral backgrounds. Contrary to previous claims, we find that selection on the FADS regions, associated with fatty acid metabolism, began before the Neolithisation of Europe. Similarly, the lactase persistence allele started increasing in frequency before the expansion of Steppe-related groups into Europe and has continued to increase up to the present. Along the genetic cline separating Mesolithic hunter-gatherers from Neolithic farmers, we find significant correlations with trait associations related to skin disorders, diet and lifestyle and mental health status, suggesting marked phenotypic differences between these groups with very different lifestyles. This work provides new insights into major transformations in recent human evolution, elucidating the complex interplay between selection and admixture that shaped patterns of genetic variation in modern populations.

Summary The Eurasian Holocene (beginning c. 12 thousand years ago) encompassed some of the most significant changes in human evolution, with far-reaching consequences for the dietary, physical and mental health of present-day populations. Using an imputed dataset of >1600 complete ancient genome sequences, and new computational methods for locating selection in time and space, we reconstructed the selection landscape of the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify major selection signals related to metabolism, possibly associated with the dietary shift occurring in this period. We show that the selection on loci such as the FADS cluster, associated with fatty acid metabolism, and the lactase persistence locus, began earlier than previously thought. A substantial amount of selection is also found in the HLA region and other loci associated with immunity, possibly due to the increased exposure to pathogens during the Neolithic, which may explain the current high prevalence of auto-immune disease, such as psoriasis, due to genetic trade-offs. By using ancient populations to infer local ancestry tracks in hundreds of thousands of samples from the UK Biobank, we find strong genetic differentiation among ancient Europeans in loci associated with anthropometric traits and susceptibility to several diseases that contribute to present-day disease burden. These were previously thought to be caused by local selection, but in fact can be attributed to differential genetic contributions from various source populations that are ancestral to present-day Europeans. Thus, alleles associated with increased height seem to have increased in frequency following the Yamnaya migration into northwestern Europe around 5,000 years ago. Alleles associated with increased risk of some mood-related phenotypes are overrepresented in the farmer ancestry component entering Europe from Anatolia around 11,000 years ago, while western hunter-gatherers show a strikingly high contribution of alleles conferring risk of traits related to diabetes. Our results paint a picture of the combined contributions of migration and selection in shaping the phenotypic landscape of present-day Europeans that suggests a combination of ancient selection and migration, rather than recent local selection, is the primary driver of present-day phenotypic differences in Europe.

Multiple sclerosis (MS) is a modern neuro-inflammatory and -degenerative disease, which is most prevalent in Northern Europe. Whilst it is known that inherited risk to MS is located within or within close proximity to immune genes it is unknown when, where and how this genetic risk originated. By using the largest ancient genome dataset from the Stone Age, along with new Medieval and post-Medieval genomes, we show that many of the genetic risk variants for MS rose to higher frequency among pastoralists located on the Pontic Steppe, and were brought into Europe by the Yamnaya-related migration approximately 5,000 years ago. We further show that these MS-associated immunogenetic variants underwent positive selection both within the Steppe population, and later in Europe, likely driven by pathogenic challenges coinciding with dietary and lifestyle environmental changes. This study highlights the critical importance of this period as a determinant of modern immune responses and its subsequent impact on the risk of developing MS in a changing environment.