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Admixture has been a pervasive phenomenon in human history, extensively shaping the patterns of population genetic diversity. There is increasing evidence to suggest that admixture can also facilitate genetic adaptation to local environments, i.e., admixed populations acquire beneficial mutations from source populations, a process that we refer to as "adaptive admixture." However, the role of adaptive admixture in human evolution and the power to detect it remain poorly characterized. Here, we use extensive computer simulations to evaluate the power of several neutrality statistics to detect natural selection in the admixed population, assuming multiple admixture scenarios. We show that statistics based on admixture proportions, F adm and LAD, show high power to detect mutations that are beneficial in the admixed population, whereas other statistics, including iHS and F ST , falsely detect neutral mutations that have been selected in the source populations only. By combining F adm and LAD into a single, powerful statistic, we scanned the genomes of 15 worldwide, admixed populations for signatures of adaptive admixture. We confirm that lactase persistence and resistance to malaria have been under adaptive admixture in West Africans and in Malagasy, North Africans, and South Asians, respectively. Our approach also uncovers other cases of adaptive admixture, including APOL1 in Fulani nomads and PKN2 in East Indonesians, involved in resistance to infection and metabolism, respectively. Collectively, our study provides evidence that adaptive admixture has occurred in human populations whose genetic history is characterized by periods of isolation and spatial expansions resulting in increased gene flow., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Tuberculosis (TB), usually caused by Mycobacterium tuberculosis bacteria, is the first cause of death from an infectious disease at the worldwide scale, yet the mode and tempo of TB pressure on humans remain unknown. The recent discovery that homozygotes for the P1104A polymorphism of TYK2 are at higher risk to develop clinical forms of TB provided the first evidence of a common, monogenic predisposition to TB, offering a unique opportunity to inform on human co-evolution with a deadly pathogen. Here, we investigate the history of human exposure to TB by determining the evolutionary trajectory of the TYK2 P1104A variant in Europe, where TB is considered to be the deadliest documented infectious disease. Leveraging a large dataset of 1,013 ancient human genomes and using an approximate Bayesian computation approach, we find that the P1104A variant originated in the common ancestors of West Eurasians ∼30,000 years ago. Furthermore, we show that, following large-scale population movements of Anatolian Neolithic farmers and Eurasian steppe herders into Europe, P1104A has markedly fluctuated in frequency over the last 10,000 years of European history, with a dramatic decrease in frequency after the Bronze Age. Our analyses indicate that such a frequency drop is attributable to strong negative selection starting ∼2,000 years ago, with a relative fitness reduction on homozygotes of 20%, among the highest in the human genome. Together, our results provide genetic evidence that TB has imposed a heavy burden on European health over the last two millennia., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The hemoglobin β S 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 β S 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 β S 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 β S 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 β S in the ancestors of present-day agriculturalist populations ∼22,000 years ago. Furthermore, we show that rainforest hunter-gatherers have more recently acquired the β S 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., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000-13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change-containing variation acquired from archaic hominins or adaptive variants in specific populations-improving our understanding of the relative biological importance of innate immunity pathways in natural conditions., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Host-pathogen interactions are generally initiated by host recognition of microbial components or danger signals triggered by microbial invasion. This recognition involves germline-encoded microbial sensors or pattern-recognition receptors (PRRs). By studying the way in which natural selection has driven the evolution of these microbial sensors in humans, we can identify genes playing an essential role and distinguish them from other, more redundant genes. We characterized the sequence diversity of the NOD-like receptor family, including the NALP and NOD/IPAF subfamilies, in various populations worldwide and compared this diversity with that of other PRR families, such as Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs). We found that most NALPs had evolved under strong selective constraints, suggesting that their functions are essential and possibly much broader than previously thought. Conversely, most NOD/IPAF subfamily members were subject to more relaxed selective constraints, suggesting greater redundancy. Furthermore, some NALP genes, including NLRP1, NLRP14, and CIITA, were found to have evolved adaptively. We identified those variants conferring a selective advantage on some human populations as the most likely targets of positive selection. More generally, the strength of selection differed considerably between the major families of microbial sensors. Endosomal TLRs and most NALPs were found to evolve under stronger purifying selection than most NOD/IPAF subfamily members and cell-surface TLRs and RLRs, suggesting some degree of redundancy in the signaling pathways triggered by these molecules. This study provides novel perspectives and experimentally testable hypotheses concerning the relative biological relevance of the various families of microbial sensors in humans., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

MicroRNAs (miRNAs) are noncoding RNAs involved in posttranscriptional gene repression, and their role in diverse physiological processes is increasingly recognized. Yet, few efforts have been devoted to evolutionary studies of human miRNAs. Knowledge about the way in which natural selection has targeted miRNAs should provide insight into their functional relevance as well as their mechanisms of action. Here we used miRNAs as a model system for investigating the influence of natural selection on gene regulation by characterizing the full spectrum of naturally occurring sequence variation of 117 human miRNAs from different populations worldwide. We found that purifying selection has globally constrained the diversity of miRNA-containing regions and has strongly targeted the mature miRNA. This observation emphasizes that mutations in these molecules are likely to be deleterious, and therefore they can have severe phenotypic consequences on human health. More importantly, we obtained evidence of population-specific events of positive selection acting on a number of miRNA-containing regions. Notably, our analysis revealed that positive selection has targeted a "small-RNA-rich island" on chromosome 14, harboring both miRNAs and small nucleolar RNAs, in Europeans and East Asians. These observations support the notion that the tuning of gene expression contributes to the processes by which populations adapt to specific environments. These findings will fuel future investigations exploring how genetic and functional variation of miRNAs under selection affects the repression of their mRNA targets, increasing our understanding of the role of gene regulation in population adaptation and human disease.