EGAGenomicsEtienne Patinhttps://ega-archive.org/dacs/EGAC00001000139EGAEGA DAC EGAC00001000139EGAepatin@pasteur.frThe genetic history of African populations is increasingly well documented, yet their patterns of epigenomic variation remain uncharacterized. Moreover, the relative impacts of DNA sequence variation and temporal changes in lifestyle and habitat on the human epigenome remain unknown. Here we generate genome-wide genotype and DNA methylation profiles for 362 rainforest hunter-gatherers and sedentary farmers. We find that the current habitat and historical lifestyle of a population have similarly critical impacts on the methylome, but the biological functions affected strongly differ. Specifically, methylation variation associated with recent changes in habitat mostly concerns immune and cellular functions, whereas that associated with historical lifestyle affects developmental processes. Furthermore, methylation variation--particularly that correlated with historical lifestyle--shows strong associations with nearby genetic variants that, moreover, are enriched in signals of natural selection. Our work provides new insight into the genetic and environmental factors affecting the epigenomic landscape of human populations over time.Understanding how deleterious genetic variation is distributed across human populations is of key importance in evolutionary biology and medical genetics. However, the impact of population size changes and gene flow on the corresponding mutational load remains a controversial topic. Here, we report high-coverage exomes from 300 rainforest hunter-gatherers and farmers of central Africa, whose distinct subsistence strategies are expected to have impacted their demographic pasts. Detailed demographic inference indicates that hunter-gatherers and farmers recently experienced population collapses and expansions, respectively, accompanied by increased gene flow. We show that the distribution of deleterious alleles across these populations is compatible with a similar efficacy of selection to remove deleterious variants with additive effects, and predict with simulations that their present-day additive mutation load is almost identical. For recessive mutations, although an increased load is predicted for hunter-gatherers, this increase has probably been partially counteracted by strong gene flow from expanding farmers. Collectively, our predicted and empirical observations suggest that the impact of the recent population decline of African hunter-gatherers on their mutation load has been modest and more restrained than would be expected under a fully recessive model of dominance.Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.The evolutionary history of the human pygmy phenotype (small body size), a characteristic of African and Southeast Asian rainforest hunter-gatherers, is largely unknown. Here we use a genome-wide admixture mapping analysis to identify 16 genomic regions that are significantly associated with the pygmy phenotype in the Batwa, a rainforest hunter-gatherer population from Uganda (east central Africa). The identified genomic regions have multiple attributes that provide supporting evidence of genuine association with the pygmy phenotype, including enrichments for SNPs previously associated with stature variation in Europeans and for genes with growth hormone receptor and regulation functions. To test adaptive evolutionary hypotheses, we computed the haplotype-based integrated haplotype score (iHS) statistic and the level of population differentiation (FST) between the Batwa and their agricultural neighbors, the Bakiga, for each genomic SNP. Both |iHS| and FST values were significantly higher for SNPs within the Batwa pygmy phenotype-associated regions than the remainder of the genome, a signature of polygenic adaptation. In contrast, when we expanded our analysis to include Baka rainforest hunter-gatherers from Cameroon and Gabon (west central Africa) and Nzebi and Nzime neighboring agriculturalists, we did not observe elevated |iHS| or FST values in these genomic regions. Together, these results suggest adaptive and at least partially convergent origins of the pygmy phenotype even within Africa, supporting the hypothesis that small body size confers a selective advantage for tropical rainforest hunter-gatherers but raising questions about the antiquity of this behavior.The demographic history and mutational load of African hunter-gatherers and farmers.The epigenomic landscape of African rainforest hunter-gatherers and farmers.Adaptive, convergent origins of the pygmy phenotype in African rainforest hunter-gatherers.Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.Perry George H GH, Foll Matthieu M, Grenier Jean-Christophe JC, Patin Etienne E, Nédélec Yohann Y, Pacis Alain A, Barakatt Maxime M, Gravel Simon S, Zhou Xiang X, Nsobya Sam L SL, Excoffier Laurent L, Quintana-Murci Lluis L, Dominy Nathaniel J NJ, Barreiro Luis B LBLopez Marie M, Kousathanas Athanasios A, Quach Hélène H, Harmant Christine C, Mouguiama-Daouda Patrick P, Hombert Jean-Marie JM, Froment Alain A, Perry George H GH, Barreiro Luis B LB, Verdu Paul P, Patin Etienne E, Quintana-Murci Lluís LQuach Hélène H, Rotival Maxime M, Pothlichet Julien J, Loh Yong-Hwee Eddie YE, Dannemann Michael M, Zidane Nora N, Laval Guillaume G, Patin Etienne E, Harmant Christine C, Lopez Marie M, Deschamps Matthieu M, Naffakh Nadia N, Duffy Darragh D, Coen Anja A, Leroux-Roels Geert G, Clément Frederic F, Boland Anne A, Deleuze Jean-François JF, Kelso Janet J, Albert Matthew L ML, Quintana-Murci Lluis LFagny Maud M, Patin Etienne E, MacIsaac Julia L JL, Rotival Maxime M, Flutre Timothée T, Jones Meaghan J MJ, Siddle Katherine J KJ, Quach Hélène H, Harmant Christine C, McEwen Lisa M LM, Froment Alain A, Heyer Evelyne E, Gessain Antoine A, Betsem Edouard E, Mouguiama-Daouda Patrick P, Hombert Jean-Marie JM, Perry George H GH, Barreiro Luis B LB, Kobor Michael S MS, Quintana-Murci Lluis Ltweenase activity, tween-hydrolyzing esterase activity, takedo 1969-4-9, triacylglycerol acylhydrolase activity, triglyceride hydrolase activity, PPL, post-heparin plasma protamine-resistant lipase, salt-resistant post-heparin lipase, tributyrinase activity, triglyceridase activity, tributyrin esterase activity, cacordase activity., lipazin, hepatic monoacylglycerol acyltransferase, heparin releasable hepatic lipase, glycerol ester hydrolase activity, glycerol-ester hydrolase activity, tributyrase activity, amano B, tweenesterase activity, GA 56, amano P, triacylglycerol lipase activity, TAG activity, hepatic lipase, triacetinase activity, GEH, amano CE, amano CES, meito sangyo OF lipase, amno N-AP, tween hydrolase activity, capalase L, butyrinase activity, meito MY 30, liver lipase, triolein hydrolase activity, triacylglycerol ester hydrolase activity, amano AP, steapsinFarmworkers, Demographers, Prehistoric, Stable Population, Aspect, Demographies, Farm Workers, Reverse Survival Methods, Factor, Historical Aspects, Technic, historical aspects, Historical Aspect, Agricultural Workers, Demographic Impact, Historical Demography, Impact, Demographic and Health Survey, Period Analysis, Demographic Surveys, Period Analyses, Period, Method, Demographer, Distributions, Demographic, Impacts, Population Spatial Distribution, Survey, Population Methods, Workers, Analysis, Stable Population Methods, Distribution, Spatial Distributions, Reconstitution, Technique, Prehistoric Demography, Demographic and Health Surveys, Population Spatial, Methods, Population Spatial Distributions, Population Distribution, Demography, Family Reconstitutions, Demographic Analysis, Accounting, Brass, Agricultural Worker., Factors, Demographic Analyses, Analyses, Reconstitutions, Reverse Survival Method, Rancher, Prehistoric Demographies, Demographics, Demographic Factor, Population, Stable Population Method, Histories, Worker, Brass Technique, Demographic Impacts, Demographic Factors, Spatial Distribution, Demographic Accounting, 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