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The selection landscape and genetic legacy of ancient Eurasians

Irving-Pease, Evan K., Refoyo-Martínez, Alba, Barrie, William, Ingason, Andrés, Pearson, Alice, Fischer, Anders, Sjögren, Karl-Göran, Halgren, Alma S., Macleod, Ruairidh, Demeter, Fabrice, Henriksen, Rasmus A., Vimala, Tharsika, McColl, Hugh, Vaughn, Andrew H., Speidel, Leo, Stern, Aaron J., Scorrano, Gabriele, Ramsøe, Abigail, Schork, Andrew J., Rosengren, Anders, Zhao, Lei, Kristiansen, Kristian, Iversen, Astrid K. N., Fugger, Lars, Sudmant, Peter H., Lawson, Daniel J., Durbin, Richard, Korneliussen, Thorfinn, Werge, Thomas, Allentoft, Morten E., Sikora, Martin, Nielsen, Rasmus, Racimo, Fernando, Willerslev, Eske·2024·Nature
DOI 10.1038/s41586-023-06705-1PMC PMC10781624

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Abstract

The Holocene (beginning around 12,000 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 a dataset of more than 1,600 imputed ancient genomes 1 , we modelled the selection landscape during the transition from hunting and gathering, to farming and pastoralism across West Eurasia. We identify key selection signals related to metabolism, including that selection at the FADS cluster began earlier than previously reported and that selection near the LCT locus predates the emergence of the lactase persistence allele by thousands of years. We also find strong selection in the HLA region, possibly due to increased exposure to pathogens during the Bronze Age. Using ancient individuals to infer local ancestry tracts in over 400,000 samples from the UK Biobank, we identify widespread differences in the distribution of Mesolithic, Neolithic and Bronze Age ancestries across Eurasia. By calculating ancestry-specific polygenic risk scores, we show that height differences between Northern and Southern Europe are associated with differential Steppe ancestry, rather than selection, and that risk alleles for mood-related phenotypes are enriched for Neolithic farmer ancestry, whereas risk alleles for diabetes and Alzheimer’s disease are enriched for Western hunter-gatherer ancestry. Our results indicate that ancient selection and migration were large contributors to the distribution of phenotypic diversity in present-day Europeans.

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Figures

Fig. 1 Geographic and temporal distribution of the 1,015 ancient genomes from West Eurasia. a, Map of West Eurasia showing sampling locations and ages of the ancient samples. b, Raincloud plot of the sample ages, grouped by sampling region: Western Europe (n = 156), Central/Eastern Europe (n = 268), Southern Europe (n = 136), Northern Europe (n = 432) and Central/Western Asia (n = 23). Boxplot shows the median and first and third quartiles of the sample ages and whiskers extend to the largest value no further than 1.5× the interquartile range.
Fig. 1 Geographic and temporal distribution of the 1,015 ancient genomes from West Eurasia. a, Map of West Eurasia showing sampling locations and ages of the ancient samples. b, Raincloud plot of the sample ages, grouped by sampling region: Western Europe (n = 156), Central/Eastern Europe (n = 268), Southern Europe (n = 136), Northern Europe (n = 432) and Central/Western Asia (n = 23). Boxplot shows the median and first and third quartiles of the sample ages and whiskers extend to the largest value no further than 1.5× the interquartile range.CC BY · PubMed Central
Fig. 2 The genetic legacy of ancient Eurasian ancestries in present-day populations. a–e, Maps showing the average ancestry of: WHG (a); EHG (b); CHG (c); Neolithic farmer (d); and Steppe pastoralist (e) ancestry components per country (left) and per county or unitary authority within Great Britain and per country for the Republic of Ireland and Northern Ireland (right). Estimation was performed using ChromoPainter and NNLS, on samples of a ‘typical ancestral background’ for each non-UK country (n = 24,511) and Northern Ireland. For Great Britain, an average of self-identified ‘white British’ samples was used to represent each UK county and unitary authority, based on place of birth (n = 408,884). Countries with less than 4 and counties with less than 15 samples are shown in grey. Map uses ArcGIS layers World Countries Generalized and World Terrain.
Fig. 2 The genetic legacy of ancient Eurasian ancestries in present-day populations. a–e, Maps showing the average ancestry of: WHG (a); EHG (b); CHG (c); Neolithic farmer (d); and Steppe pastoralist (e) ancestry components per country (left) and per county or unitary authority within Great Britain and per country for the Republic of Ireland and Northern Ireland (right). Estimation was performed using ChromoPainter and NNLS, on samples of a ‘typical ancestral background’ for each non-UK country (n = 24,511) and Northern Ireland. For Great Britain, an average of self-identified ‘white British’ samples was used to represent each UK county and unitary authority, based on place of birth (n = 408,884). Countries with less than 4 and counties with less than 15 samples are shown in grey. Map uses ArcGIS layers World Countries Generalized and World Terrain.CC BY · PubMed Central
Fig. 3 A schematic of the model of population structure in Europe. Quantitative admixture model used to simulate genomes to train the local ancestry neural network classifier. The model begins with the Out-of-Africa population, before splitting into basal Northern Europeans (NE) and West Asians (WA), who further split into EHG, WHG, CHG and ANA. These then admix to form Steppe pastoralist (Yam) and Neolithic farmer (Neo) populations. Moving down the figure is forwards in time and the population split times and admixture times are given in generations ago. Each branch is labelled with the effective population size of the population. Coloured lines represent the populations declared in the simulation that extend through time.
Fig. 3 A schematic of the model of population structure in Europe. Quantitative admixture model used to simulate genomes to train the local ancestry neural network classifier. The model begins with the Out-of-Africa population, before splitting into basal Northern Europeans (NE) and West Asians (WA), who further split into EHG, WHG, CHG and ANA. These then admix to form Steppe pastoralist (Yam) and Neolithic farmer (Neo) populations. Moving down the figure is forwards in time and the population split times and admixture times are given in generations ago. Each branch is labelled with the effective population size of the population. Coloured lines represent the populations declared in the simulation that extend through time.CC BY · PubMed Central
Fig. 4 Genome-wide selection scan for trait-associated variants. a, Manhattan plot of P values from selection scan with CLUES, based on a time-series of imputed aDNA genotype probabilities. Twenty-one genome-wide significant selection peaks highlighted in grey and labelled with the gene closest to the most significant SNP within each locus. Within each sweep, SNPs are positioned on the y axis and coloured by their most significant marginal ancestry. Outside of the sweeps, SNPs show P values from the pan-ancestry analysis and are coloured grey. Red dotted lines indicate genome-wide significance (P < 5 × 10−8). b, Detailed plots for three genome-wide significant sweep loci: (1) MCM6, lactase persistence; (2) SLC45A2, skin pigmentation; and (3) FADS2, lipid metabolism. Rows show results for the pan-ancestry analysis (ALL) plus the four marginal ancestries: WHG, EHG, CHG and ANA. The first column of each locus shows zoomed Manhattan plots of the P values for each ancestry and column two shows allele frequency trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Fig. 4 Genome-wide selection scan for trait-associated variants. a, Manhattan plot of P values from selection scan with CLUES, based on a time-series of imputed aDNA genotype probabilities. Twenty-one genome-wide significant selection peaks highlighted in grey and labelled with the gene closest to the most significant SNP within each locus. Within each sweep, SNPs are positioned on the y axis and coloured by their most significant marginal ancestry. Outside of the sweeps, SNPs show P values from the pan-ancestry analysis and are coloured grey. Red dotted lines indicate genome-wide significance (P < 5 × 10−8). b, Detailed plots for three genome-wide significant sweep loci: (1) MCM6, lactase persistence; (2) SLC45A2, skin pigmentation; and (3) FADS2, lipid metabolism. Rows show results for the pan-ancestry analysis (ALL) plus the four marginal ancestries: WHG, EHG, CHG and ANA. The first column of each locus shows zoomed Manhattan plots of the P values for each ancestry and column two shows allele frequency trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Fig. 5 ARSs for 35 complex traits. Showing the genetic risk that a present-day individual would possess if they were composed entirely of one ancestry. On the basis of chromosome painting of the UKB, for 35 complex traits found to be significantly overdispersed in ancient populations. Confidence intervals (95%) are estimated by bootstrapping present-day samples (n = 408,884) and centred on the mean estimate.
Fig. 5 ARSs for 35 complex traits. Showing the genetic risk that a present-day individual would possess if they were composed entirely of one ancestry. On the basis of chromosome painting of the UKB, for 35 complex traits found to be significantly overdispersed in ancient populations. Confidence intervals (95%) are estimated by bootstrapping present-day samples (n = 408,884) and centred on the mean estimate.CC BY · PubMed Central
Extended Data Fig. 1 Selection at the MCM6 locus. CLUES selection results for the most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 1 Selection at the MCM6 locus. CLUES selection results for the most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 2 Selection at the SLC45A2 locus. CLUES selection results for the second most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 2 Selection at the SLC45A2 locus. CLUES selection results for the second most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 3 Selection at the HLA locus. CLUES selection results for the third most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 3 Selection at the HLA locus. CLUES selection results for the third most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 4 Selection at the ACAD10 locus. CLUES selection results for the fourth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 4 Selection at the ACAD10 locus. CLUES selection results for the fourth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 5 Selection at the CCDC12 locus. CLUES selection results for the fifth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 5 Selection at the CCDC12 locus. CLUES selection results for the fifth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 6 Selection at the RNA5SP158 locus. CLUES selection results for the sixth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 6 Selection at the RNA5SP158 locus. CLUES selection results for the sixth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 7 Selection at the GATA4 locus. CLUES selection results for the seventh most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 7 Selection at the GATA4 locus. CLUES selection results for the seventh most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 8 Selection at the ARL17B locus. CLUES selection results for the eighth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 8 Selection at the ARL17B locus. CLUES selection results for the eighth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 9 Selection at the IRF1 locus. CLUES selection results for the ninth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 9 Selection at the IRF1 locus. CLUES selection results for the ninth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 10 Selection at the KRT18P51 locus. CLUES selection results for the tenth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).
Extended Data Fig. 10 Selection at the KRT18P51 locus. CLUES selection results for the tenth most significant sweep locus, showing the pan-ancestry analysis (ALL) plus the four marginal ancestries: Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) and Anatolian farmers (ANA). Row one shows zoomed Manhattan plots of the p values for each ancestry and row two shows allele trajectories for the top SNPs across all ancestries (grey shading for the marginal ancestries indicates approximate temporal extent of the pre-admixture population).CC BY · PubMed Central
Extended Data Fig. 11 The 17q21.31 inversion locus. A) Haplotypes of the 17q21.31 locus: the ancestral (non-inverted) H1 17q21.31 and the inverted H2 haplotype. Duplications of the KANSL1 gene have occurred independently on both lineages yielding H1D and H2D haplotypes. B) Frequency of the 17q21.31 inversion and duplication haplotypes across present-day global populations (Human Genome Diversity Project82). C) Change in the frequency of the 17q21.31 inversion haplotype through time.
Extended Data Fig. 11 The 17q21.31 inversion locus. A) Haplotypes of the 17q21.31 locus: the ancestral (non-inverted) H1 17q21.31 and the inverted H2 haplotype. Duplications of the KANSL1 gene have occurred independently on both lineages yielding H1D and H2D haplotypes. B) Frequency of the 17q21.31 inversion and duplication haplotypes across present-day global populations (Human Genome Diversity Project82). C) Change in the frequency of the 17q21.31 inversion haplotype through time.CC BY · PubMed Central

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Metadata

Authors
Irving-Pease, E. K., Refoyo-Martínez, A., Barrie, W., Ingason, A., Pearson, A., Fischer, A., Sjögren, K.-G., Halgren, A. S., Macleod, R., Demeter, F., Henriksen, R. A., Vimala, T., McColl, H., Vaughn, A. H., Speidel, L., Stern, A. J., Scorrano, G., Ramsøe, A., Schork, A. J., Rosengren, A., Zhao, L., Kristiansen, K., Iversen, A. K. N., Fugger, L., Sudmant, P. H., Lawson, D. J., Durbin, R., Korneliussen, T., Werge, T., Allentoft, M. E., Sikora, M., Nielsen, R., Racimo, F., & Willerslev, E.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2024-01-10
Volume
625
Issue
7994
Pages
312-320
ISSN
  • 0028-0836
  • 1476-4687
DOI
10.1038/s41586-023-06705-1
PMC
PMC10781624
Cited by
126
References
23
Language
en
Licence

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