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Post by Admin on May 14, 2022 18:49:34 GMT
Fig. 9 A. First two principal components of a PCA of ancient Western Eurasian samples, coloured by height polygenic scores. B. Top 6 UK Biobank trait-association components from DeGAs that have the highest correlation (P < 5e-3) with the principal component separating ancient farmers from hunter-gatherer populations (PC1 in Panel A). C. Top UK Biobank traits with highest overdispersion in polygenic scores among ancient populations, out of a total of 320 sets of trait-associated SNPs tested (QX > 79.4, P < 0.05/320). We used these Neolithic hunter-gatherer clusters (“postNeol” ancestry source set, Extended data Fig. 4) as putative source groups in more proximal admixture modelling to investigate the spatiotemporal dynamics of ancestry compositions across the Steppe and Lake Baikal after the Neolithic period. We replicate previously reported evidence for a genetic shift towards higher Forest Steppe hunter-gatherer ancestry (SteppeCE_7000BP_3600BP) in late Neolithic and early Bronze Age individuals (LNBA) at Lake Baikal 93, 94. However, ancestry related to this cluster is already observed at ∼7,000 BP in herein-reported Neolithic hunter-gatherer individuals both at Lake Baikal (NEO199, NEO200), and along the Angara river to the north (NEO843). Both male individuals at Lake Baikal belonged to Y-chromosome haplogroup Q1, characteristic of the later LNBA groups in the same region. (Extended Data Fig. 3, 6A). Together with an estimated date of admixture of ∼6,000 BP for the LNBA groups, these results suggest gene flow between hunter-gatherers of Lake Baikal and the south Siberian forest steppe regions already during the early Neolithic. This is consistent with archaeological interpretations of contact. In this region, bifacially flaked tools first appeared near Baikal 95 from where the technique spread far to the west. We find its reminiscences in Late Neolithic archaeological complexes (Shiderty 3, Borly, Sharbakty 1, Ust-Narym, etc.) in Northern and Eastern Kazakhstan, around 6,500-6,000 BP 96, 97. Our herein-reported genomes also shed light on the genetic origins of the early Bronze Age Okunevo culture in the Minusinsk Basin in Southern Siberia. In contrast to previous results, we find no evidence for Lake Baikal hunter-gatherer ancestry in the Okunevo93, 94, suggesting that they instead originate from a three-way mixture of two different genetic clusters of Siberian forest steppe hunter-gatherers and Steppe-related ancestry (Extended data Fig. 4D). We date the admixture with Steppe-related ancestry to ∼4,600 BP, consistent with gene flow from peoples of the Afanasievo culture that existed near Altai and Minusinsk Basin during the early eastwards’ expansion of Yamnaya-related groups 20, 94. From around 3,700 BP, individuals across the Steppe and Lake Baikal regions display markedly different ancestry profiles (Fig. 3; Extended Data Fig. 4D, 9). We document a sharp increase in non-local ancestries, with only limited ancestry contributions from local hunter-gatherers. The early stages of this transition are characterised by influx of Yamnaya-related ancestry, which decays over time from its peak of ∼70% in the earliest individuals. Similar to the dynamics in western Eurasia, Yamnaya-related ancestry is here correlated with late Neolithic GAC-related farmer ancestry (Poland_5000BP_4700BP; Extended data Fig. 9G), recapitulating the previously documented eastward expansion of admixed Western Steppe pastoralists from the Sintashta and Andronovo complexes during the Bronze Age20, 48, 98. However, GAC-related ancestry is notably absent in individuals of the Okunevo culture, providing further support for two distinct eastward migrations of Western Steppe pastoralists during the early (Yamnaya) and later (Sintashta, Andronovo) Bronze Age. The later stages of the transition are characterised by increasing Central Asian (Turkmenistan_7000 BP_5000BP) and Northeast Asian-related (Amur_7500BP) ancestry components (Extended data Fig. 9G). Together, these results show that deeply structured hunter-gatherer ancestry dominated the eastern Eurasian Steppe substantially longer than in western Eurasia, before successive waves of population expansions swept across the Steppe within the last 4,000 years, including a large-scale introduction of domesticated horse lineages concomitant with new equestrian equipment and spoke-wheeled chariotry 20, 48, 98, 99.
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Post by Admin on May 15, 2022 18:07:38 GMT
Genetic legacy of Stone Age Europeans To investigate the distribution of Stone Age and Early Bronze Age ancestry components in modern populations, we used ChromoPainter 100 to “paint” the chromosomes of individuals in the UK Biobank (https://www.ukbiobank.ac.uk) using a panel of 10 ancient donor populations (Supplementary Note 3h). Painting was done following the pipeline of Margaryan et al. 101 based on GLOBETROTTER 102, and admixture proportions were estimated using Non-Negative Least squares. Haplotypes in the modern genomes are assigned to the genetically closest ancient population as measured by meiosis events, which favours more recent matches in time. Therefore, ancestry proportions assigned to the oldest groups (e.g. WHG) should be interpreted as an excess of this ancestry, which cannot be explained by simply travelling through more recent ancient populations up to present times.
First, we selected non-British individuals from the UK Biobank if their country of birth was European, African, or Asian. Because many of these individuals are admixed or British, we set up a pipeline (Supplementary Note 3g) to select individuals of a typical ancestral background for each country. This resulted in 24,511 individuals from 126 countries, who were then chromosome painted to assess the average admixture proportions for each ancestry per country.
The various hunter-gatherer ancestries are not homogeneously distributed amongst modern populations (Fig. 5). WHG-related ancestry is highest in present-day individuals from the Baltic States, Belarus, Poland, and Russia; EHG-related ancestry is highest in Mongolia, Finland, Estonia and Central Asia; and CHG-related ancestry is maximised in countries east of the Caucasus, in Pakistan, India, Afghanistan and Iran, in accordance with previous results 103. The CHG-related ancestry likely reflects both Caucasus hunter-gatherer and Iranian Neolithic signals, explaining the relatively high levels in south Asia 104. Consistent with expectations 105, 106, Neolithic Anatolian-related farmer ancestry is concentrated around the Mediterranean basin, with high levels in southern Europe, the Near East, and North Africa, including the Horn of Africa, but is less frequent in Northern Europe. This is in direct contrast to the Steppe-related ancestry, which is found in high levels in northern Europe, peaking in Ireland, Iceland, Norway, and Sweden, but decreases further south. There is also evidence for its spread into southern Asia. Overall, these results refine global patterns of spatial distributions of ancient ancestries amongst modern populations.
The availability of a large number of modern genomes (n=408,884) from self-identified “white” British individuals who share similar PCA backgrounds 107 allowed us to further examine the distribution of ancient ancestries at high resolution in Britain (Supplementary Note 3h). Although regional ancestry distributions differ by only a few percent, we find clear evidence of geographical heterogeneity across the United Kingdom as visualised by assigning individuals to their birth county and averaging ancestry proportions per county (Fig. 5, inset boxes). The proportion of Neolithic farmer ancestry is highest in southern and eastern England today and lower in Scotland, Wales, and Cornwall. Steppe-related ancestry is inversely distributed, peaking in the Outer Hebrides and Ireland, a pattern only previously described for Scotland 108. This regional pattern was already evident in the Pre-Roman Iron Age and persists to the present day even though immigrating Anglo-Saxons had relatively less Neolithic farmer ancestry than the Iron-Age population of southwest Briton (Extended data Fig. 4). Although this Neolithic farmer/steppe-related dichotomy mirrors the modern ‘Anglo-Saxon’/‘Celtic’ ethnic divide, its origins are older, resulting from continuous migration from a continental population relatively enhanced in Neolithic farmer ancestry, starting as early as the Late Bronze Age 109. By measuring haplotypes from these ancestries in modern individuals, we are able to show that these patterns differentiate Wales and Cornwall as well as Scotland from England. We also found higher levels of WHG-related ancestry in central and Northern England. These results demonstrate clear ancestry differences within an ‘ethnic group’ (white British) traditionally considered relatively homogenous, which highlights the need to account for subtle population structure when using resources such as the UK Biobank genomes.
Sociocultural insights We used patterns of pairwise IBD sharing between individuals and runs of homozygosity (ROH) within individuals (measured as the fraction of the genome within a run of homozygosity f(ROH)) to examine our data for temporal shifts in relatedness within genetic clusters. Both measures show clear trends of a reduction of within-cluster relatedness over time, in both western and eastern Eurasia (Fig. 6). This pattern is consistent with a scenario of increasing effective population sizes during this period 110. Nevertheless, we observe notable differences in temporal relatedness patterns between western and eastern Eurasia, mirroring the wider difference in population dynamics discussed above. In the west, within-group relatedness changes substantially during the Neolithic transition (∼9,000 to ∼6,000 BP), where clusters of Neolithic farmer-associated individuals show overall reduced IBD sharing and f(ROH) compared to clusters of HG-associated individuals (Fig. 6A,C). In the east, genetic relatedness remains high until ∼4,000 BP, consistent with a much longer persistence of smaller localised hunter-gatherer groups (Fig. 6B,D).
Next, we examined the data for evidence of recent parental relatedness, by identifying individuals harbouring a large fraction of their genomes (> 50cM) in long (>20cM) ROH segments 111. We only detect 39 such individuals out of a total sample of 1,540 imputed ancient genomes (Fig. 6E), in line with recent results indicating that close kin mating was not common in human prehistory 41, 103, 111, 112. With the exception of eight ancient American individuals from the San Nicolas Islands in California 113, no obviously discernible spatiotemporal or cultural clustering was observed among the individuals with recent parental relatedness. Interestingly, an ∼1,700-year-old Sarmatian individual from Temyaysovo (tem003) 114 was found homozygous for almost the entirety of chromosome 2, but without evidence of ROHs elsewhere in the genome, suggesting an ancient case of uniparental disomy. Among several noteworthy familial relationships (see Supplementary Fig. S3c.2), we report a Mesolithic father/son burial at Ertebølle (NEO568/NEO569), as well as a Mesolithic mother/daughter burial at Dragsholm (NEO732/NEO733).
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Post by Admin on May 15, 2022 22:38:06 GMT
Pathogenic structural variants in ancient vs. modern-day humans Rare, recurrent copy-number variants (CNVs) are known to cause neurodevelopmental disorders and are associated with a range of psychiatric and physical traits with variable expressivity and incomplete penetrance115, 116. To understand the prevalence of pathogenic structural variants over time we examined 50 genomic regions susceptible to recurrent CNV, known to be the most prevalent drivers of human developmental pathologies117. The analysis included 1442 ancient imputed genomes passing quality control for CNV analysis (Supplementary Note 4i) and 1093 modern human genomes for comparison 118, 119. We identified CNVs in ancient individuals at ten loci using a read-depth based approach and digital Comparative Genomic Hybridization 120 (Supplementary Table S4i.1; Supplementary Figs. S4i.1-S41.20). Although most of the observed CNVs (including duplications at 15q11.2 and CHRNA7, and CNVs spanning parts of the TAR locus and 22q11.2 distal) have not been unambiguously associated with disease in large studies, the identified CNVs include deletions and duplications that have been associated with developmental delay, dysmorphic features, and neuropsychiatric abnormalities such as autism (most notably at 1q21.1, 3q29, 16p12.1 and the DiGeorge/VCFS locus, but also deletions at 15q11.2 and duplications at 16p13.11). The individual harbouring the 16p13.1 deletion, RISE586 20, a 4,000 BP woman aged 20-30 from the Únětice culture (modern day Czech Republic), had almost complete skeletal remains, which allowed us to test for the presence of various skeletal abnormalities associated with the 16p13.11 microdeletion 121. RISE586 exhibited a hypoplastic tooth, spondylolysis of the L5 vertebrae, incomplete coalescence of the S1 sacral bone, among other minor skeletal phenotypes. The skeletal phenotypes observed in this individual are relatively common (∼10%) in European populations and are not specific to 16p13.1 thus do not indicate strong penetrance of this mutation in RISE586 122–125. However, these results do highlight our ability to link putatively pathogenic genotypes to phenotypes in ancient individuals. Overall, the carrier frequency in the ancient individuals is similar to that reported in the UK Biobank genomes (1.25% vs 1.6% at 15q11.2 and CHRNA7 combined, and 0.8% vs 1.1% across the remaining loci combined) 126. These results suggest that large, recurrent CNVs that can lead to several pathologies were present at similar frequencies in the ancient and modern populations included in this study.
Ancestry-stratified patterns of natural selection in the last 13,000 years The Neolithic transition led to a fundamental change in lifestyle, diet and exposure to pathogens that imposed drastically new selection pressures on human populations. To detect genetic candidate targets of selection, we used a set of 1,015 imputed ancient genomes from West Eurasia that were fitted to a four-way admixture model of demographic history in this region (Supplementary Note 3i) and identified phenotype-associated variants with evidence for directional selection over the last 13,000 years, with a special focus on the Neolithic transition (Supplementary Note 4a). We adapted CLUES 127 to model time-series data (Supplementary Note 4a) and used it to infer allele frequency trajectories and selection coefficients for 33,323 quality-controlled phenotype-associated variants ascertained from the GWAS Catalogue 128. An equal number of putatively neutral, frequency-paired variants were used as a control set. To control for possible confounders, we built a causal model to distinguish direct effects of age on allele frequency from indirect effects mediated by read depth, read length, and/or error rates (Supplementary Note 4b), and developed a mapping bias test used to evaluate systematic differences between data from ancient and present-day populations (Supplementary Note 4a). Because admixture between groups with differing allele frequencies can confound interpretation of allele frequency changes through time, we also applied a novel chromosome painting technique, based on inference of a sample’s nearest neighbours in the marginal trees of a tree sequence (Supplementary Note 3i). This allowed us to accurately assign ancestral path labels to haplotypes found in both ancient and present-day individuals. By conditioning on these haplotype path labels, we could infer selection trajectories while controlling for changes in admixture proportions through time (Supplementary Note 4a).
Our analysis identified no genome-wide significant (p < 5e-8) selective sweeps when using genomes from present-day individuals alone (1000 Genomes Project populations GBR, FIN and TSI), although trait-associated variants were enriched for signatures of selection compared to the control group (p < 2.2e-16, Wilcoxon signed-rank test). In contrast, when using imputed aDNA genotype probabilities, we identified 11 genome-wide significant selective sweeps in the GWAS variants, and none in the control group, consistent with selection acting on trait-associated variants (Supplementary Note 4a, Supplementary Figs. S4a.4 to S4a.14). However, when conditioned on one of our four ancestral histories—genomic regions arriving in present day genomes through Western hunter-gatherers (WHG), Eastern hunter-gatherers (EHG), Caucasus hunter-gatherers (CHG) or Anatolian farmers (ANA)—we identified 21 genome-wide significant selection peaks (including the 11 from the pan-ancestry analysis) (Fig. 7). This suggests that admixture between ancestral populations has masked evidence of selection at many trait associated loci in modern populations.
Selection on diet-associated loci We find strong changes in selection associated with lactose digestion after the introduction of farming, but prior to the expansion of the Yamnaya pastoralists into Europe around 5,000 years ago 20, 21, settling controversies regarding the timing of this selection 129–132. The strongest overall signal of selection in the pan-ancestry analysis is observed at the MCM6 / LCT locus (rs4988235; p=9.86e-31; s=0.020), where the derived allele results in lactase persistence 133, 134 (Supplementary Note 4a). The trajectory inferred from the pan-ancestry analysis indicates that the lactase persistence allele began increasing in frequency only c. 7,000 years ago, and has continued to increase up to present times (Fig. 7). Our ancestry-stratified analysis shows, however, that selection at the MCM6/LCT locus is much more complex than previously thought. In the pan-ancestry analysis, this sweep is led by the lactase persistence SNP rs4988235, whereas in the ancestry-stratified analysis, this signal is primarily driven by sweeps in two of the ancestral backgrounds (EHG and CHG), each of which differ in their most significant SNPs (Fig. 7). Conversely, in the WHG background, we find no evidence for selection at rs4988235, but strong selection at rs12465802 within the last c. 2,000 years. Overall, our results suggest that there were multiple, asynchronous selective sweeps in this genomic region in recent human history, and possibly targeting different loci.
We also find strong selection in the FADS gene cluster — FADS1 (rs174546; p=2.65e-10; s=0.013) and FADS2 (rs174581; p=1.87e-10; s=0.013) — which are associated with fatty acid metabolism and known to respond to changes in diet from a more/less vegetarian to a more/less carnivorous diet 135–140. In contrast to previous results 138–140, we find that much of the selection associated with a more vegetarian diet occurred in Neolithic populations before they arrived in Europe, but then continued during the Neolithic (Fig. 7). The strong signal of selection in this region in the pan-ancestry analysis is driven primarily by a sweep occurring on the EHG, CHG and ANA haplotypic backgrounds (Fig. 7). Interestingly, we find no evidence for selection at this locus in the WHG background, and most of the allele frequency rise in the EHG background occurs after their admixture with CHG (around 8ka, 141), within whom the selected alleles were already close to present-day frequencies. This suggests that the selected alleles may already have existed at substantial frequencies in early farmer populations in the Middle East and among Caucasus Hunter gatherers (associated with the ANA and CHG and backgrounds, respectively) and were subject to continued selection as eastern groups moved northwards and westwards during the late Neolithic and Bronze Age periods.
When specifically comparing selection signatures differentiating ancient hunter-gatherer and farmer populations 142, we also observe a large number of regions associated with lipid and sugar metabolism, and various metabolic disorders (Supplementary Note 4e). These include, for example, a region in chromosome 22 containing PATZ1, which regulates the expression of FADS1, and MORC2, which plays an important role in cellular lipid metabolism 143–145. Another region in chromosome 3 overlaps with GPR15, which is both related to immune tolerance and to intestinal homeostasis 146–148. Finally, in chromosome 18, we recover a selection candidate region spanning SMAD7, which is associated with inflammatory bowel diseases such as Crohn’s disease 149–151.
Taken together these results suggest that the transition to agriculture imposed a substantial amount of selection for humans to adapt to our new diet and that some diseases observed today in modern societies can likely be understood as a consequence of this selection.
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Post by Admin on May 16, 2022 17:51:35 GMT
Selection on immunity-associated variants In addition to diet-related selection, we observe selection in several loci associated with immunity/defence functions and with autoimmune disease (Supplementary Note 4a). Some of these selection events occurred earlier than previously claimed and are likely associated with the transition to agriculture and may help explain the high prevalence of autoimmune diseases today. Most notably, we detect a 33 megabase (Mb) wide selection sweep signal in chromosome 6 (chr6:19.1–50.9 Mb), spanning the human leukocyte antigen (HLA) region (Supplementary Note 4a). The selection trajectories of the variants within this locus support multiple independent sweeps, occurring at different times and with differing intensities. The strongest signal of selection at this locus in the pan-ancestry analysis is at an intergenic variant, located between HLA-A and HLA-W (rs7747253; p=8.86e-17; s=-0.018), associated with heel bone mineral density 152, the derived allele of which rapidly reduced in frequency, beginning c. 8,000 years ago (Extended Data Fig. 10). In contrast, the signal of selection at C2 (rs9267677; p= 9.82e-14; s= 0.04463), also found within this sweep, and associated with educational attainment 153, shows a gradual increase in frequency beginning c. 4,000 years ago, before rising more rapidly c. 1,000 years ago. This highlights the complex temporal dynamics of selection at the HLA locus, which not only plays a role in the regulation of the immune system, but also has association with many other non-immune-related phenotypes. The high pleiotropy in this region makes it difficult to determine which selection pressures may have driven these increases in frequencies at different periods of time. However, profound shifts in lifestyle in Eurasian populations during the Holocene, including a change in diet and closer contact with domestic animals, combined with higher mobility and increasing population sizes, are likely drivers for strong selection on loci involved in immune response.
We also identified selection signals at the SLC22A4 (rs35260072; p=1.15e-10; s=0.018) locus, associated with increased itch intensity from mosquito bites 154, and find that the derived variant has been steadily rising in frequency since c. 9,000 years ago (Extended Data Fig. 11). However, in the same SLC22A4 candidate region as rs35260072, we find that the frequency of the previously reported SNP rs1050152 plateaued c. 1,500 years ago, contrary to previous reports suggesting a recent rise in frequency 45. Similarly, we detect selection at the HECTD4 (rs11066188; p=3.02e-16; s=0.020) and ATXN2 (rs653178; p=1.92e-15; s=0.019) locus, associated with celiac disease and rheumatoid arthritis 155, which has been rising in frequency for c. 9,000 years (Extended Data Fig. 12), also contrary to previous reports of a more recent rise in frequency 45. Thus, several disease-associated loci previously thought to be the result of recent adaptation may have been subject to selection for a longer period of time.
Selection on the 17q12.13 locus We further detect signs of strong selection in a 12 Mb sweep in chromosome 17 (chr17:36.1–48.1 Mb), spanning a locus on 17q21.3 implicated in neurodegenerative and developmental disorders (Supplementary Note 4a). The locus includes an inversion and other structural polymorphisms with indications of a recent positive selection sweep in some human populations 156, 157. Specifically, partial duplications of the KANSL1 gene likely occurred independently on the inverted (H2) and non-inverted (H1) haplotypes (Fig. 8B) and both are found in high frequencies (15-25%) among current European and Middle Eastern populations but are much rarer in Sub-Saharan African and East Asian populations. We used both SNP genotypes and WGS read depth information to determine inversion (H1/H2) and KANSL1 duplication (d) status in the ancient individuals studied here (see Supplementary Note 4g).
The H2 haplotype is observed in two of three previously published genomes158 of Anatolian aceramic Neolithic individuals (Bon001 and Bon004) from around 10,000 BP, but data were insufficient to identify KANSL1 duplications. The oldest evidence for KANSL1 duplications is observed in an Iranian early Neolithic individual (AH1 from 9,900 BP2) followed by two Georgian Mesolithic individuals (NEO281 from 9,724 BP and KK1 6 from 9,720 BP) all of whom are heterozygous for the inversion and carry the inverted duplication. The KANSL1 duplications are also detected in two Russian Neolithic individuals: NEO560 from 7,919 BP (H1d) and NEO212 from 7,390 BP (H2d). With both H1d and H2d having spread to large parts of Europe with Anatolian Neolithic Farmer ancestry, their frequency seems unchanged in most of Europe as Steppe-related ancestry becomes dominant in large parts of the subcontinent (Extended data Fig. 8D). The fact that both H1d and H2d are found in apparently high frequencies in both early Anatolian Farmers and the earliest Yamnaya/Steppe-related ancestry groups suggests that any selective sweep acting on the H1d and H2d variants would probably have occurred in populations ancestral to both.
We note that the strongest signal of selection observed in this locus is at MAPT (rs4792897; p=4.65e-10; s=0.03 (Fig. 8A; Supplementary Note 4a), which codes for the tau protein 159 and is involved in a number of neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease 160–164. However, the region is also enriched for evidence of reference bias in our imputed dataset—especially around the KANSL1 gene—due to complex structural polymorphisms (Supplementary Note 4i).
Selection on pigmentation-associated variants Our results identify strong selection for lighter skin pigmentation in groups moving northwards and westwards, in agreement with the hypothesis that selection is caused by reduced UV exposure and resulting vitamin D deficiency. We find that the most strongly selected alleles reached near-fixation several thousand years ago, suggesting that this was not associated with recent sexual selection as proposed 165, 166 (Supplementary Note 4a).
In the pan-ancestry analysis we detect strong selection at the SLC45A2 locus (rs35395; p=4.13e-23; s=0.022) locus 167, 168, with the selected allele (responsible for lighter skin), increasing in frequency from c. 13,000 years ago, until plateauing c. 2,000 years ago (Fig. 7). The dominating hypothesis is that high melanin levels in the skin are important in equatorial regions owing to its protection against UV radiation, whereas lighter skin has been selected for at higher latitudes (where UV radiation is less intense) because some UV penetration is required for cutaneous synthesis of vitamin D 169, 170. Our findings confirm pigmentation alleles as major targets of selection during the Holocene 45, 171, 172 particularly on a small proportion of loci with large effect sizes 168.
Additionally, our results provide unprecedentedly detailed information about the duration and geographic spread of these processes (Fig. 7) suggesting that an allele associated with lighter skin was selected for repeatedly, probably as a consequence of similar environmental pressures occurring at different times in different regions. In the ancestry-stratified analysis, all marginal ancestries show broad agreement at the SLC45A2 locus (Fig. 7) but differ in the timing of their frequency shifts. The ANA ancestry background shows the earliest evidence for selection, followed by EHG and WHG around c. 10,000 years ago, and CHG c. 2,000 years later. In all ancestry backgrounds except WHG, the selected haplotypes reach near fixation by c. 3,000 years ago, whilst the WHG haplotype background contains the majority of ancestral alleles still segregating in present-day Europeans. This finding suggests that selection on this allele was much weaker in ancient western hunter-gatherer groups during the Holocene compared to elsewhere. We also detect strong selection at the SLC24A5 (rs1426654; p=6.45e-09; s=0.019) which is also associated with skin pigmentation 167, 173. At this locus, the selected allele increased in frequency even earlier than SLC45A2 and reached near fixation c. 3,500 years ago (Supplementary Note 4a). Selection on this locus thus seems to have occurred early on in groups that were moving northwards and westwards, and only later in the Western hunter-gatherer background after these groups encountered and admixed with the incoming populations.
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Post by Admin on May 17, 2022 0:58:20 GMT
Selection among major axes of ancient population variation Beyond patterns of genetic change at the Mesolithic-Neolithic transition, much genetic variability observed today reflects high genetic differentiation in the hunter-gatherer groups that eventually contributed to modern European genetic diversity 142. Indeed, a substantial number of loci associated with cardiovascular disease, metabolism and lifestyle diseases trace their genetic variability prior to the Neolithic transition, to ancient differential selection in ancestry groups occupying different parts of the Eurasian continent (Supplementary Note 4d). These may represent selection episodes that preceded the admixture events described above, and led to differentiation between ancient hunter-gatherer groups in the late Pleistocene and early Holocene. One of these overlaps with the SLC24A3 gene which is a salt sensitivity gene significantly expressed in obese individuals 174, 175. Another spans ROPN1 and KALRN, two genes involved in vascular disorders 176–178. A further region contains SLC35F3, which codes for a thiamine transport and has been associated with hypertension in a Han Chinese cohort 179, 180. Finally, there is a candidate region containing several genes (CH25H, FAS) associated with obesity and lipid metabolism 181–183 and another peak with several genes (ASXL2, RAB10, HADHA, GPR113) involved in glucose homeostasis and fatty acid metabolism 184–193. These loci predominantly reflect ancient patterns of extreme differentiation between Eastern and Western Eurasian genomes, and may be candidates for selection after the separation of the Pleistocene populations that occupied different environments across the continent (roughly 45,000 years ago 103).
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