Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.

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.

Genomic insights into population history and biological adaptation in Oceania.

The Pacific region is of major importance for addressing questions regarding human dispersals, interactions with archaic hominins and natural selection processes1. However, the demographic and adaptive history of Oceanian populations remains largely uncharacterized. Here we report high-coverage genomes of 317 individuals from 20 populations from the Pacific region. We find that the ancestors of Papuan-related ('Near Oceanian') groups underwent a strong bottleneck before the settlement of the region, and separated around 20,000-40,000 years ago. We infer that the East Asian ancestors of Pacific populations may have diverged from Taiwanese Indigenous peoples before the Neolithic expansion, which is thought to have started from Taiwan around 5,000 years ago2-4. Additionally, this dispersal was not followed by an immediate, single admixture event with Near Oceanian populations, but involved recurrent episodes of genetic interactions. Our analyses reveal marked differences in the proportion and nature of Denisovan heritage among Pacific groups, suggesting that independent interbreeding with highly structured archaic populations occurred. Furthermore, whereas introgression of Neanderthal genetic information facilitated the adaptation of modern humans related to multiple phenotypes (for example, metabolism, pigmentation and neuronal development), Denisovan introgression was primarily beneficial for immune-related functions. Finally, we report evidence of selective sweeps and polygenic adaptation associated with pathogen exposure and lipid metabolism in the Pacific region, increasing our understanding of the mechanisms of biological adaptation to island environments.

Recent Adaptive Acquisition by African Rainforest Hunter-Gatherers of the Late Pleistocene Sickle-Cell Mutation Suggests Past Differences in Malaria Exposure.

The hemoglobin ßS sickle mutation is a textbook case in which natural selection maintains a deleterious mutation at high frequency in the human population. Homozygous individuals for this mutation develop sickle-cell disease, whereas heterozygotes benefit from higher protection against severe malaria. Because the overdominant ßS allele should be purged almost immediately from the population in the absence of malaria, the study of the evolutionary history of this iconic mutation can provide important information about the history of human exposure to malaria. Here, we sought to increase our understanding of the origins and time depth of the ßS mutation in populations with different lifestyles and ecologies, and we analyzed the diversity of HBB in 479 individuals from 13 populations of African farmers and rainforest hunter-gatherers. Using an approximate Bayesian computation method, we estimated the age of the ßS allele while explicitly accounting for population subdivision, past demography, and balancing selection. When the effects of balancing selection are taken into account, our analyses indicate a single emergence of ßS in the ancestors of present-day agriculturalist populations ∼22,000 years ago. Furthermore, we show that rainforest hunter-gatherers have more recently acquired the ßS mutation from the ancestors of agriculturalists through adaptive gene flow during the last ∼6,000 years. Together, our results provide evidence for a more ancient exposure to malarial pressures among the ancestors of agriculturalists than previously appreciated, and they suggest that rainforest hunter-gatherers have been increasingly exposed to malaria during the last millennia.

The Genetic Legacy of the Indian Ocean Slave Trade: Recent Admixture and Post-admixture Selection in the Makranis of Pakistan.

From the eighth century onward, the Indian Ocean was the scene of extensive trade of sub-Saharan African slaves via sea routes controlled by Muslim Arab and Swahili traders. Several populations in present-day Pakistan and India are thought to be the descendants of such slaves, yet their history of admixture and natural selection remains largely undefined. Here, we studied the genome-wide diversity of the African-descent Makranis, who reside on the Arabian Sea coast of Pakistan, as well that of four neighboring Pakistani populations, to investigate the genetic legacy, population dynamics, and tempo of the Indian Ocean slave trade. We show that the Makranis are the result of an admixture event between local Baluch tribes and Bantu-speaking populations from eastern or southeastern Africa; we dated this event to ∼300 years ago during the Omani Empire domination. Levels of parental relatedness, measured through runs of homozygosity, were found to be similar across Pakistani populations, suggesting that the Makranis rapidly adopted the traditional practice of endogamous marriages. Finally, we searched for signatures of post-admixture selection at traits evolving under positive selection, including skin color, lactase persistence, and resistance to malaria. We demonstrate that the African-specific Duffy-null blood group-believed to confer resistance against Plasmodium vivax infection-was recently introduced to Pakistan through the slave trade and evolved adaptively in this P. vivax malaria-endemic region. Our study reconstructs the genetic and adaptive history of a neglected episode of the African Diaspora and illustrates the impact of recent admixture on the diffusion of adaptive traits across human populations.

The Basque paradigm: genetic evidence of a maternal continuity in the Franco-Cantabrian region since pre-Neolithic times.

Different lines of evidence point to the resettlement of much of western and central Europe by populations from the Franco-Cantabrian region during the Late Glacial and Postglacial periods. In this context, the study of the genetic diversity of contemporary Basques, a population located at the epicenter of the Franco-Cantabrian region, is particularly useful because they speak a non-Indo-European language that is considered to be a linguistic isolate. In contrast with genome-wide analysis and Y chromosome data, where the problem of poor time estimates remains, a new timescale has been established for the human mtDNA and makes this genome the most informative marker for studying European prehistory. Here, we aim to increase knowledge of the origins of the Basque people and, more generally, of the role of the Franco-Cantabrian refuge in the postglacial repopulation of Europe. We thus characterize the maternal ancestry of 908 Basque and non-Basque individuals from the Basque Country and immediate adjacent regions and, by sequencing 420 complete mtDNA genomes, we focused on haplogroup H. We identified six mtDNA haplogroups, H1j1, H1t1, H2a5a1, H1av1, H3c2a, and H1e1a1, which are autochthonous to the Franco-Cantabrian region and, more specifically, to Basque-speaking populations. We detected signals of the expansion of these haplogroups at ∼4,000 years before present (YBP) and estimated their separation from the pan-European gene pool at ∼8,000 YBP, antedating the Indo-European arrival to the region. Our results clearly support the hypothesis of a partial genetic continuity of contemporary Basques with the preceding Paleolithic/Mesolithic settlers of their homeland.

A 1,100-year-old founder effect mutation in IL12B gene is responsible for Mendelian susceptibility to mycobacterial disease in Tunisian patients.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder predisposing apparently healthy individuals to infections caused by weakly virulent mycobacteria such as bacille Calmette-Guerin (BCG), environmental mycobacteria, and poorly virulent Salmonella strains. IL-12p40 deficiency is the first reported human disease due to a cytokine gene defect and is one of the deficiencies that cause MSMD. Nine mutant alleles only have been identified in the IL12B gene, and three of them are recurrent mutations due to a founder effect in specific populations. IL-12p40 deficiency has been identified especially in countries where consanguinity is high and where BCG vaccination at birth is universal. We investigated, in such settings, the clinical, cellular, and molecular features of six IL-12p40-deficient Tunisian patients having the same mutation in IL12B gene (c.298_305del). We found that this mutation is inherited as a common founder mutation arousing ~1,100 years ago. This finding facilitates the development of a preventive approach by genetic counseling and prenatal diagnosis especially in affected families.

Evidence of pre-Roman tribal genetic structure in Basques from uniparentally inherited markers.

Basque people have received considerable attention from anthropologists, geneticists, and linguists during the last century due to the singularity of their language and to other cultural and biological characteristics. Despite the multidisciplinary efforts performed to address the questions of the origin, uniqueness, and heterogeneity of Basques, the genetic studies performed up to now have suffered from a weak study design where populations are not analyzed in an adequate geographic and population context. To address the former questions and to overcome these design limitations, we have analyzed the uniparentally inherited markers (Y chromosome and mitochondrial DNA) of ~900 individuals from 18 populations, including those where Basque is currently spoken and populations from adjacent regions where Basque might have been spoken in historical times. Our results indicate that Basque-speaking populations fall within the genetic Western European gene pool, that they are similar to geographically surrounding non-Basque populations, and also that their genetic uniqueness is based on a lower amount of external influences compared with other Iberians and French populations. Our data suggest that the genetic heterogeneity and structure observed in the Basque region result from pre-Roman tribal structure related to geography and might be linked to the increased complexity of emerging societies during the Bronze Age. The rough overlap of the pre-Roman tribe location and the current dialect limits support the notion that the environmental diversity in the region has played a recurrent role in cultural differentiation and ethnogenesis at different time periods.

Strong maternal Khoisan contribution to the South African coloured population: a case of gender-biased admixture.

The study of recently admixed populations provides unique tools for understanding recent population dynamics, socio-cultural factors associated with the founding of emerging populations, and the genetic basis of disease by means of admixture mapping. Historical records and recent autosomal data indicate that the South African Coloured population forms a unique highly admixed population, resulting from the encounter of different peoples from Africa, Europe, and Asia. However, little is known about the mode by which this admixed population was recently founded. Here we show, through detailed phylogeographic analyses of mitochondrial DNA and Y-chromosome variation in a large sample of South African Coloured individuals, that this population derives from at least five different parental populations (Khoisan, Bantus, Europeans, Indians, and Southeast Asians), who have differently contributed to the foundation of the South African Coloured. In addition, our analyses reveal extraordinarily unbalanced gender-specific contributions of the various population genetic components, the most striking being the massive maternal contribution of Khoisan peoples (more than 60%) and the almost negligible maternal contribution of Europeans with respect to their paternal counterparts. The overall picture of gender-biased admixture depicted in this study indicates that the modern South African Coloured population results mainly from the early encounter of European and African males with autochthonous Khoisan females of the Cape of Good Hope around 350 years ago.

Unravelling the determinants of human health in French Polynesia: the MATAEA project.

Background: French Polynesia is a French overseas collectivity in the Southeast Pacific, comprising 75 inhabited islands across five archipelagoes. The human settlement of the region corresponds to the last massive migration of humans to empty territories, but its timeline is still debated. Despite their recent population history and geographical isolation, inhabitants of French Polynesia experience health issues similar to those of continental countries. Modern lifestyles and increased longevity have led to a rise in non-communicable diseases (NCDs) such as obesity, diabetes, hypertension, and cardiovascular diseases. Likewise, international trade and people mobility have caused the emergence of communicable diseases (CDs) including mosquito-borne and respiratory diseases. Additionally, chronic pathologies including acute rheumatic fever, liver diseases, and ciguatera, are highly prevalent in French Polynesia. However, data on such diseases are scarce and not representative of the geographic fragmentation of the population. Objectives: The present project aims to estimate the prevalence of several NCDs and CDs in the population of the five archipelagoes, and identify associated risk factors. Moreover, genetic analyses will contribute to determine the sequence and timings of the peopling history of French Polynesia, and identify causal links between past genetic adaptation to island environments, and present-day susceptibility to certain diseases. Methods: This cross-sectional survey is based on the random selection of 2,100 adults aged 18-69 years and residing on 18 islands from the five archipelagoes. Each participant answered a questionnaire on a wide range of topics (including demographic characteristics, lifestyle habits and medical history), underwent physical measurements (height, weight, waist circumference, arterial pressure, and skin pigmentation), and provided biological samples (blood, saliva, and stool) for biological, genetic and microbiological analyses. Conclusion: For the first time in French Polynesia, the present project allows to collect a wide range of data to explore the existence of indicators and/or risk factors for multiple pathologies of public health concern. The results will help health authorities to adapt actions and preventive measures aimed at reducing the incidence of NCDs and CDs. Moreover, the new genomic data generated in this study, combined with anthropological data, will increase our understanding of the peopling history of French Polynesia. Clinical trial registration: https://clinicaltrials.gov/, identifier: NCT06133400.

The genomic landscape of contemporary western Remote Oceanians.

The Vanuatu archipelago served as a gateway to Remote Oceania during one of the most extensive human migrations to uninhabited lands ∼3,000 years ago. Ancient DNA studies suggest an initial settlement by East Asian-related peoples that was quickly followed by the arrival of Papuan-related populations, leading to a major population turnover. Yet there is uncertainty over the population processes and the sociocultural factors that have shaped the genomic diversity of ni-Vanuatu, who present nowadays among the world's highest linguistic and cultural diversity. Here, we report new genome-wide data for 1,433 contemporary ni-Vanuatu from 29 different islands, including 287 couples. We find that ni-Vanuatu derive their East Asian- and Papuan-related ancestry from the same source populations and descend from relatively synchronous, sex-biased admixture events that occurred ∼1,700-2,300 years ago, indicating a peopling history common to the whole archipelago. However, East Asian-related ancestry proportions differ markedly across islands, suggesting that the Papuan-related population turnover was geographically uneven. Furthermore, we detect Polynesian ancestry arriving ∼600-1,000 years ago to Central and South Vanuatu in both Polynesian-speaking and non-Polynesian-speaking populations. Last, we provide evidence for a tendency of spouses to carry similar genetic ancestry, when accounting for relatedness avoidance. The signal is not driven by strong genetic effects of specific loci or trait-associated variants, suggesting that it results instead from social assortative mating. Altogether, our findings provide an insight into both the genetic history of ni-Vanuatu populations and how sociocultural processes have shaped the diversity of their genomes.

A loss-of-function IFNAR1 allele in Polynesia underlies severe viral diseases in homozygotes.

Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-ß). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.

Maternal traces of deep common ancestry and asymmetric gene flow between Pygmy hunter-gatherers and Bantu-speaking farmers.

Two groups of populations with completely different lifestyles-the Pygmy hunter-gatherers and the Bantu-speaking farmers-coexist in Central Africa. We investigated the origins of these two groups and the interactions between them, by analyzing mtDNA variation in 1,404 individuals from 20 farming populations and 9 Pygmy populations from Central Africa, with the aim of shedding light on one of the most fascinating cultural transitions in human evolution (the transition from hunting and gathering to agriculture). Our data indicate that this region was colonized gradually, with an initial L1c-rich ancestral population ultimately giving rise to current-day farmers, who display various L1c clades, and to Pygmies, in whom L1c1a is the only surviving clade. Detailed phylogenetic analysis of complete mtDNA sequences for L1c1a showed this clade to be autochthonous to Central Africa, with its most recent branches shared between farmers and Pygmies. Coalescence analyses revealed that these two groups arose through a complex evolutionary process characterized by (i) initial divergence of the ancestors of contemporary Pygmies from an ancestral Central African population no more than approximately 70,000 years ago, (ii) a period of isolation between the two groups, accounting for their phenotypic differences, (iii) long-standing asymmetric maternal gene flow from Pygmies to the ancestors of the farming populations, beginning no more than approximately 40,000 years ago and persisting until a few thousand years ago, and (iv) enrichment of the maternal gene pool of the ancestors of the farming populations by the arrival and/or subsequent demographic expansion of L0a, L2, and L3 carriers.

Genomic Evidence for Local Adaptation of Hunter-Gatherers to the African Rainforest.

African rainforests support exceptionally high biodiversity and host the world's largest number of active hunter-gatherers [1-3]. The genetic history of African rainforest hunter-gatherers and neighboring farmers is characterized by an ancient divergence more than 100,000 years ago, together with recent population collapses and expansions, respectively [4-12]. While the demographic past of rainforest hunter-gatherers has been deeply characterized, important aspects of their history of genetic adaptation remain unclear. Here, we investigated how these groups have adapted-through classic selective sweeps, polygenic adaptation, and selection since admixture-to the challenging rainforest environments. To do so, we analyzed a combined dataset of 566 high-coverage exomes, including 266 newly generated exomes, from 14 populations of rainforest hunter-gatherers and farmers, together with 40 newly generated, low-coverage genomes. We find evidence for a strong, shared selective sweep among all hunter-gatherer groups in the regulatory region of TRPS1-primarily involved in morphological traits. We detect strong signals of polygenic adaptation for height and life history traits such as reproductive age; however, the latter appear to result from pervasive pleiotropy of height-associated genes. Furthermore, polygenic adaptation signals for functions related to responses of mast cells to allergens and microbes, the IL-2 signaling pathway, and host interactions with viruses support a history of pathogen-driven selection in the rainforest. Finally, we find that genes involved in heart and bone development and immune responses are enriched in both selection signals and local hunter-gatherer ancestry in admixed populations, suggesting that selection has maintained adaptive variation in the face of recent gene flow from farmers.

The demographic history and mutational load of African hunter-gatherers and farmers.

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.

Dispersals and genetic adaptation of Bantu-speaking populations in Africa and North America.

Bantu languages are spoken by about 310 million Africans, yet the genetic history of Bantu-speaking populations remains largely unexplored. We generated genomic data for 1318 individuals from 35 populations in western central Africa, where Bantu languages originated. We found that early Bantu speakers first moved southward, through the equatorial rainforest, before spreading toward eastern and southern Africa. We also found that genetic adaptation of Bantu speakers was facilitated by admixture with local populations, particularly for the HLA and LCT loci. Finally, we identified a major contribution of western central African Bantu speakers to the ancestry of African Americans, whose genomes present no strong signals of natural selection. Together, these results highlight the contribution of Bantu-speaking peoples to the complex genetic history of Africans and African Americans.

Sub-Saharan African coding sequence variation and haplotype diversity at the NAT2 gene.

A total of 530 chromosomes from 12 sub-Saharan African populations were sequenced at the human arylamine N-acetyltransferase NAT2 gene. We identified seven novel non-synonymous mutations observed at low frequencies (<11%) in our African multi-ethnic panel. By using algorithms based on evolutionary conservation, two mutations (c.70T>A [p.L24I] and c.578C>T [p.T193M]) for which the activity of their encoded protein has never been determined, were predicted to entail a potentially damaging effect on protein activity. In addition, approximately 5% of the overall NAT2 African haplotypes presented an unknown functional effect. More interestingly, NAT2 haplotype frequencies and acetylation status inference revealed that the hunter-gatherer Western Pygmies and !Kung San were mainly composed of fast and intermediate acetylators, in clear contrast with most agriculturalist populations. These observations highlight the need of a detailed genetic characterization of African populations at this locus to adapt medical treatment, such as the antitubercular isoniazid, to individual/population make-up in the most effective manner.

Origins, admixture and founder lineages in European Roma.

The Roma, also known as 'Gypsies', represent the largest and the most widespread ethnic minority of Europe. There is increasing evidence, based on linguistic, anthropological and genetic data, to suggest that they originated from the Indian subcontinent, with subsequent bottlenecks and undetermined gene flow from/to hosting populations during their diaspora. Further support comes from the presence of Indian uniparentally inherited lineages, such as mitochondrial DNA M and Y-chromosome H haplogroups, in a significant number of Roma individuals. However, the limited resolution of most genetic studies so far, together with the restriction of the samples used, have prevented the detection of other non-Indian founder lineages that might have been present in the proto-Roma population. We performed a high-resolution study of the uniparental genomes of 753 Roma and 984 non-Roma hosting European individuals. Roma groups show lower genetic diversity and high heterogeneity compared with non-Roma samples as a result of lower effective population size and extensive drift, consistent with a series of bottlenecks during their diaspora. We found a set of founder lineages, present in the Roma and virtually absent in the non-Roma, for the maternal (H7, J1b3, J1c1, M18, M35b, M5a1, U3, and X2d) and paternal (I-P259, J-M92, and J-M67) genomes. This lineage classification allows us to identify extensive gene flow from non-Roma to Roma groups, whereas the opposite pattern, although not negligible, is substantially lower (up to 6.3%). Finally, the exact haplotype matching analysis of both uniparental lineages consistently points to a Northwestern origin of the proto-Roma population within the Indian subcontinent.

The epigenomic landscape of African rainforest hunter-gatherers and farmers.

The 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.