The Selection Landscape and Genetic Legacy of Ancient Eurasians

Abstract

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.

Mapping the genetic evolutionary timeline of human neural and cognitive traits

“…First, recent genetic modifications in the modern-day human genome reveal a particular enrichment for psychiatric traits (e.g. depression, alcohol intake; see Figure 2 and Table S1), in line with recent evidence showing that introgressed variants from Neanderthals (variants relatively recent in human evolution, ∼50,000 years ago) are linked to smoking, alcohol consumption, and mood-related traits 49 ; and with findings of an overrepresentation of alleles conferring risk for mood-related traits specifically in the genomes of ancient farmers (∼11,000 years old), but not in the genomes of evolutionarily earlier hunter-gatherer 50 . Second, genetic variants associated with intelligence, educational attainment, hippocampal volume, and psychiatric disorders appear to have a more recent evolutionary age than expected considering their polygenicity and MAF, suggesting the potential action of selection pressures on these phenotypes (Supplementary Results, Table S2).…”

“…Second, recent genetic modifications in the modern-day human genome reveal a particular enrichment for psychiatric traits (e.g. depression, alcohol intake; SI Appendix), in line with recent evidence showing that introgressed variants from Neanderthals (variants relatively recent in human evolution) are linked to smoking, alcohol consumption, and mood-related traits (48); and with findings of an overrepresentation of alleles conferring risk for mood-related traits specifically in ancient farmers genome (~11,000 years old) but not in evolutionary previous hunter-gatherer genome (49). Third, genes related to neuropsychiatric conditions (SCZ, BD, and AD) were found to contain more recent genetic modifications compared to other genes.…”

Ultra-fast genome-wide inference of pairwise coalescence times

“…We recover approximately 20 candidate loci, including for example LCT [18], the gene encoding the lactase enzyme, and the HLA region, both known to have been under recent positive selection in Europeans (Figure 4b). The peak at chromosome 12 falls inside HECTD4, which has recently been found to be under selection in Eurasians [13], though we note that the credible interval contains other genes.…”

Hunter-gatherer admixture facilitated natural selection in Neolithic European farmers

“…Previous studies of natural selection in the European Neolithic have either compared allele frequencies or haplotype structure with other ancient and modern populations. 5 , 11 – 14 However, no study to date has specifically attempted to identify adaptive admixture, despite the fact that this mode of adaptation has been repeatedly observed in humans. A recent study identified two optimal approaches to detect adaptive admixture in data from present-day populations, based on allele frequencies and local ancestry.…”

“…We note that the HLA appears to be a frequent target of natural selection and the processes described above are not exclusive. Extensive evidence of selection has been detected both in scans focusing on the past few millennia, 5 , 11 , 14 , 52 , 58 and following introgression from archaic humans. 54 , 59 Future studies, including whole-genome shotgun data in tandem with improved functional annotation, may shed further light on this adaptive process.…”