Anthropologie, Génétique des Populations & Immunogénétique

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Human leukocyte antigen (HLA) genes are among the most polymorphic of our genome, as a likely consequence of balancing selection related to their central role in adaptive immunity. HLA-A and HLA-B genes were recently suggested to evolve through a model of joint divergent asymmetric selection conferring all populations, including those with severe loss of diversity, an equivalent immune potential. However, the mechanisms by which these two genes might undergo joint evolution while displaying very distinct allelic profiles in populations worldwide are still unknown. To address this issue, we carried out extensive data analyses (among which factorial correspondence and linear modelling) on 2,909 common and rare HLA-A, HLA-B and HLA-C alleles and 200,000 simulated pathogenic peptides by taking into account sequence variation, predicted peptide-binding affinity and HLA allele frequencies in 123 populations worldwide. Our results show that HLA-A and HLA-B (but not HLA-C) molecules maintain considerable functional divergence in almost all populations, which likely plays an instrumental role in their immune defence. We also provide robust evidence of functional complementarity between HLA-A and HLA-B molecules, which display asymmetric relationships in terms of amino acid diversity at both inter- and intra-protein levels and in terms of promiscuous or fastidious peptide-binding specificities. Like two wings of a flying bird, the functional complementarity of HLA-A and HLA-B is a perfect example, in our genome, of duplicated genes sharing their capacity of assuming common vital functions while being submitted to complex and sometimes distinct environmental pressures.

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Many species are threatened with extinction as their population sizes decrease with changing environments or face novel pathogenic threats. A reduction of genetic diversity at major histocompatibility complex (MHC) genes may have dramatic effects on populations' survival, as these genes play a key role in adaptive immunity. This might be the case for chimpanzees, the MHC genes of which reveal signatures of an ancient selective sweep likely due to a viral epidemic that reduced their population size a few million years ago. To better assess how this past event affected MHC variation in chimpanzees compared to humans, we analysed several indexes of genetic diversity and linkage disequilibrium across seven MHC genes on four cohorts of chimpanzees and we compared them to those estimated at orthologous HLA genes in a large set of human populations.

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We report detailed peptide binding affinities between 438 HLA Class I and Class II proteins and complete proteomes of seven pandemic human viruses, including coronaviruses, influenza viruses and HIV-1. We contrast these affinities with HLA allele frequencies across hundreds of human populations worldwide. Statistical modelling shows that peptide binding affinities classified into four distinct categories depend on the HLA locus but that the type of virus is only a weak predictor, except in the case of HIV-1. Amongst the strong HLA binders (IC  ≤ 50), we uncovered 16 alleles (the top ones being A*02:02, B*15:03 and DRB1*01:02) binding more than 1% of peptides derived from all viruses, 9 (top ones including HLA-A*68:01, B*15:25, C*03:02 and DRB1*07:01) binding all viruses except HIV-1, and 15 (top ones A*02:01 and C*14:02) only binding coronaviruses. The frequencies of strongest and weakest HLA peptide binders differ significantly among populations from different geographic regions, with Indigenous peoples of America showing both higher frequencies of strongest and lower frequencies of weakest binders. As many HLA proteins are strong binders of peptides from distinct viral families, we discuss this result in relation to possible signatures of natural selection on HLA promiscuous alleles due to undetermined past pathogenic infections. Although highly relevant for evolutionary genetics and the development of vaccine therapies, these results should not lead to forget that individual resistance and vulnerability to diseases go beyond the sole HLA allelic affinity and depend on multiple, complex and often unknown biological, environmental and other variables. This article is protected by copyright. All rights reserved.

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An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Human leucocyte antigen (HLA) alleles and single nucleotide polymorphisms (SNPs) lying in the HLA region are known to be associated with several infectious diseases among which acquired immunodeficiency syndrome, hepatitis B, hepatitis C, tuberculosis, leprosy and malaria are highly prevalent in many human populations worldwide. Distinct approaches such as case-control comparisons, immunogenetic analyses, bioinformatic peptide-binding predictions, ancient DNA and genome-wide association studies (GWAS) have contributed to improving this knowledge during the last decade, although many results still need stronger statistical and/or functional support. The present review updates the information regarding the main HLA allele and SNP associations observed to date for six of the most widespread and some other infectious diseases, and provides a synthetic illustration of these findings on a schematic HLA genomic map. It then discusses these results by stressing the importance of integrating information on HLA population diversity in disease-association studies.

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Among the many genes involved in the metabolism of therapeutic drugs, human arylamine N-acetyltransferases (NATs) genes have been extensively studied, due to their medical importance both in pharmacogenetics and disease epidemiology. One member of this small gene family, NAT2, is established as the locus of the classic human acetylation polymorphism in drug metabolism. Current hypotheses hold that selective processes favoring haplotypes conferring lower NAT2 activity have been operating in modern humans' recent history as an adaptation to local chemical and dietary environments. To shed new light on such hypotheses, we investigated the genetic diversity of the three members of the NAT gene family in seven hominid species, including modern humans, Neanderthals and Denisovans. Little polymorphism sharing was found among hominids, yet all species displayed high NAT diversity, but distributed in an opposite fashion in chimpanzees and bonobos (Pan genus) compared to modern humans, with higher diversity in Pan species at NAT1 and lower at NAT2, while the reverse is observed in humans. This pattern was also reflected in the results returned by selective neutrality tests, which suggest, in agreement with the predicted functional impact of mutations detected in non-human primates, stronger directional selection, presumably purifying selection, at NAT1 in modern humans, and at NAT2 in chimpanzees. Overall, the results point to the evolution of divergent functions of these highly homologous genes in the different primate species, possibly related to their specific chemical/dietary environment (exposome) and we hypothesize that this is likely linked to the emergence of controlled fire use in the human lineage.

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HLA matching is a critical factor for successful allogeneic hematopoietic stem cell transplantation. For unrelated donor searches, matching is usually based on high-resolution typing at five HLA loci, looking for a 10/10 match. Some studies have proposed that further matching at the haplotype level could be beneficial for clinical outcome. In this study, we determined the phased haplotypes of 291 patients using family members and segregation analysis. The sum of ranks of the haplotypes carried by patients was used as a surrogate predictor of a successful unrelated donor search. The putative impact of haplotypes was then analyzed in a cohort of 211 recipients transplanted with 10/10 matched unrelated donors. A logistic regression analysis showed a highly significant effect of the haplotypes in the outcome of a search, but we did not find any significant effect on overall survival, graft versus host disease or relapse/progression following HSCT. This study provides useful data for the optimization of unrelated bone marrow donor searches, but does not confirm previous reports that matching at the haplotype level has a clinical impact following HSCT. Due to the extreme polymorphism of HLA genes, further studies are warranted to better understand the many factors at play.

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This paper discusses the advantages provided by next generation sequencing (NGS) compared to traditional typings or limited sequencing strategies for the characterization of HLA population diversity based on four documented examples. We also comment the limitations of this approach by highlighting pitfalls in interpreting NGS data.

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A total of 72 unrelated Mandenka individuals from Eastern Senegal, Niokholo region, were typed using Next Generation Sequencing (library preparation with the Holotype HLA X2 and MIA FORA NGS HLA Typing kits, sequencing with Illumina MiSeq, and bio-informatic processing with HLA Twin v1.1.1 (Omixon) and MIA FORA NGS software) and yielded reliable genotypes for 8 HLA loci, namely A, B, C, DRB1, DQA1, DQB1, DPA1 and DPB1.

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From a biogeographic perspective Africa is subdivided into distinct horizontal belts. Human populations living along the Sahel/Savannah belt south of the Sahara Desert have often been overshadowed by extensive studies focusing on other African populations such as hunter-gatherers or Bantu in particular. However, the Sahel together with the savannah bordering it in the south, is a challenging region where people had and still have to cope with harsh climatic conditions and show resilient behaviours. Besides exponentially growing urban populations, several local groups leading various lifestyles and speaking languages belonging to three main linguistic families still live in rural localities across that region today. Thanks to several years of consistent population sampling throughout this area, the genetic history of the African Sahelian populations has been largely reconstructed and a deeper knowledge has been acquired regarding their adaptation to peculiar environments and/or subsistence modes. Distinct exposures to pathogens - in particular malaria - likely contributed to their genetic differentiation for HLA genes. In addition, although food-producing strategies spread within the Sahel/Savannah belt relatively recently, during the last five millennia according to recent archaeological and archaeobotanical studies, remarkable amounts of genetic differences are also observed between sedentary farmers and more mobile pastoralists at multiple neutral and selected loci, reflecting both demographic effects and genetic adaptations to distinct cultural traits, such as dietary habits.

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With the aim to understand how NGS improves both our assessment of genetic variation within populations and our knowledge on HLA molecular evolution, we sequenced and analysed 8 HLA loci in a well-documented population from sub-Saharan Africa (Mandenka). The results of full-gene NGS-MiSeq sequencing compared to those obtained by traditional typing techniques or limited sequencing strategies showed that segregating sites located outside exon 2 are crucial to describe not only class I, but also class II population diversity. A comprehensive analysis of exons 2, 3, 4 and 5 nucleotide diversity at the 8 HLA loci revealed remarkable differences among these gene regions, notably a greater variation concentrated in the antigen recognition sites of class I exons 3 and some class II exons 2, likely associated to their peptide-presentation function, a lower diversity of HLA-C exon 3, possibly related to its role as a KIR ligand, and a peculiar molecular diversity of HLA-A exon 2, revealing demographic signals. Based on full-length HLA sequences, we also propose that the most frequent DRB1 allele in the studied population, DRB1*13:04, emerged from an allelic conversion involving 3 potential alleles as donors and DRB1*11:02:01 as recipient. Finally, our analysis revealed a high occurrence of the DRB1*13:04~DQA1*05:05:01~DQB1*03:19 haplotype, possibly resulting from a selective sweep due to protection to Onchorcerca volvulus, a prevalent pathogen in West Africa. This study unveils highly relevant information on the molecular evolution of HLA genes in relation to their immune function, calling for similar analyses in other populations living in contrasting environments.

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The original version of this article, unfortunately, contained an error.

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Human leukocyte antigen (HLA) genes play a key role in the immune response to infectious diseases, some of which are highly prevalent in specific environments, like malaria in sub-Saharan Africa. Former case-control studies showed that one particular HLA-B allele, B*53, was associated to malaria protection in Gambia, but this hypothesis was not tested so far within a population genetics framework. In this study, our objective was to assess whether pathogen-driven selection associated to malaria contributed to shape the HLA-B genetic landscape of Africa. To that aim, we first typed the HLA-A and -B loci in 484 individuals from 11 populations living in different environments across the Sahel, and we analysed these data together with those available for 29 other populations by using several approaches including linear modelling on various genetic, geographic and environmental parameters. In addition to relevant signatures of populations' demography and migrations history in the genetic differentiation patterns of both HLA-A and -B loci, we found that the frequencies of three HLA alleles, B*53, B*78 and A*74, were significantly associated to Plasmodium falciparum malaria prevalence, suggesting their increase through pathogen-driven selection in malaria-endemic environments. The two HLA-B alleles were further identified, by high-throughput sequencing, as B*53:01:01 (in putative linkage disequilibrium with one HLA-C allele, C*04:01:01:01) and B*78:01 in all but one individuals tested, making them appropriate candidates to malaria protection. These results highlight the role of environmental factors in the evolution of the HLA polymorphism and open key perspectives for functional studies focusing on HLA peptide-binding properties. This article is protected by copyright. All rights reserved.

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A catalogue of common and well-documented (CWD) human leukocyte antigen (HLA), previously established by the American Society for Histocompatibility and Immunogenetics (ASHI), is widely used as indicator for typing ambiguities to be resolved in tissue transplantation or for checking the universality of any HLA allele in the world. However, European population samples, which are characterized by a substantial level of genetic variation, are underrepresented in the ASHI catalogue. Therefore, the Population Genetics Working Group of the European Federation for Immunogenetics (EFI) has facilitated data collection for an European CWD catalogue.

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Human leukocyte antigen (HLA) genes are very informative in population genetics studies and their variability has been widely used to reconstruct the history of geographic and/or demographic expansions of human populations. The characterization of HLA diversity at the population level is also fundamental in clinical studies, particularly for bone marrow transplantation programs. In this study, we investigated the HLA molecular variation in Rio Grande do Sul, South Brazil, in order to identify possible regional differences across this state. More than 97,000 bone marrow donors were typed at the HLA- A, -B and -DRB1 loci and analyzed by considering two kinds of subdivisions based on both self-identified ethnicity and place of residence: (a) the official geographic subdivision defined by the Brazilian Institute of Geography and Statistics and (b) known information about the colonization history of the state. HLA allele and haplotype frequencies were estimated and compared among the defined subgroups. The results indicate a lack of correlation between genetic variation and geography and thus no clear HLA genetic structure based on geographic criteria. On the other hand, major differences were observed regarding ethnicity. In addition, local populations from Rio Grande do Sul were found to be genetically similar to their corresponding parental European populations from Germany, Italy and Portugal, as documented by historical data. Overall, this study provides a thorough characterization of the HLA genetic variation in Rio Grande do Sul and a better understanding of its demographic history, being most useful for the development of more efficient strategies in bone marrow donors' recruitment.

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The polymorphism of HLA genes can be used to reconstruct human peopling history. However, this huge diversity impairs successful matching in stem cell transplantation, a situation which has led to the recruitment of millions of donors worldwide. In parallel to the increase of recruitment, registries are progressively relying on information from population genetics to optimize their donor pools in terms of HLA variability. In this study, the HLA data of 65,000 Spanish bone marrow donors were analyzed together with 60,000 Portuguese individuals to provide a comprehensive HLA genetic map of the Iberian Peninsula. The frequencies of many alleles were shown to vary continuously across the Peninsula, either increasing or decreasing from the Mediterranean coast to the Atlantic domain or from the Strait of Gibraltar to the Pyrenees and Bay of Biscay. Similar patterns were observed for several haplotypes. In addition, within some regions neighboring provinces share a close genetic similarity. These results outline the genetic landscape of the Iberian Peninsula, and confirm that the analysis of the HLA polymorphism may reveal relevant signatures of past demographic events even when data from donor registries are used. This conclusion stimulates future developments of the Spanish registry, presented here for the first time.

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The main function of HLA class I molecules is to present pathogen-derived peptides to cytotoxic T lymphocytes. This function is assumed to drive the maintenance of an extraordinary amount of polymorphism at each HLA locus, providing an immune advantage to heterozygote individuals capable to present larger repertories of peptides than homozygotes. This seems contradictory, however, with a reduced diversity at individual HLA loci exhibited by some isolated populations. This study shows that the level of functional diversity predicted for the two HLA-A and HLA-B genes considered simultaneously is similar (almost invariant) between 46 human populations, even when a reduced diversity exists at each locus. We thus propose that HLA-A and HLA-B evolved through a model of joint divergent asymmetric selection conferring all populations an equivalent immune potential. The distinct pattern observed for HLA-C is explained by its functional evolution towards killer cell immunoglobulin-like receptor (KIR) activity regulation rather than peptide presentation.

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The diversity of killer-cell immunoglobulin-like receptors (KIR) genes was evaluated in Portuguese and the observed genotypic profiles were found related to the ones reported in European populations. The KIR repertoire after hematopoietic stem cell transplantation is determined by these gene frequencies and the KIR group B motifs are the less common. We estimated donor-KIR/recipient-ligand interactions in transplants with related donors and unrelated donors found in a local registry or from abroad. A large fraction of transplants had all three ligands of inhibitory receptors, and therefore, in theory were not prone to natural killer cell (NK) mediated alloreactivity. Furthermore, the distribution of KIR alloreactive interactions was found independent of the donor-recipient genetic proximity, probably because of different gene segregation and comparable KIR frequencies in the donor pools.

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Dietary changes associated to shifts in subsistence strategies during human evolution may have induced new selective pressures on phenotypes, as currently held for lactase persistence. Similar hypotheses exist for arylamine N-acetyltransferase 2 (NAT2) mediated acetylation capacity, a well-known pharmacogenetic trait with wide inter-individual variation explained by polymorphisms in the NAT2 gene. The environmental causative factor (if any) driving its evolution is as yet unknown, but significant differences in prevalence of acetylation phenotypes are found between hunter-gatherer and food-producing populations, both in sub-Saharan Africa and worldwide, and between agriculturalists and pastoralists in Central Asia. These two subsistence strategies also prevail among sympatric populations of the African Sahel, but knowledge on NAT2 variation among African pastoral nomads was up to now very scarce. Here we addressed the hypothesis of different selective pressures associated to the agriculturalist or pastoralist lifestyles having acted on the evolution of NAT2 by sequencing the gene in 287 individuals from five pastoralist and one agriculturalist Sahelian populations.

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Recent genetic studies have suggested that the colonization of East Asia by modern humans was more complex than a single origin from the South, and that a genetic contribution via a Northern route was probably quite substantial.

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Supertypes are groups of human leukocyte antigen (HLA) alleles which bind overlapping sets of peptides due to sharing specific residues at the anchor positions-the B and F pockets-of the peptide-binding region (PBR). HLA alleles within the same supertype are expected to be functionally similar, while those from different supertypes are expected to be functionally distinct, presenting different sets of peptides. In this study, we applied the supertype classification to the HLA-A and HLA-B data of 55 worldwide populations in order to investigate the effect of natural selection on supertype rather than allelic variation at these loci. We compared the nucleotide diversity of the B and F pockets with that of the other PBR regions through a resampling procedure and compared the patterns of within-population heterozygosity (He) and between-population differentiation (G ST) observed when using the supertype definition to those estimated when using randomized groups of alleles. At HLA-A, low levels of variation are observed at B and F pockets and randomized He and G ST do not differ from the observed data. By contrast, HLA-B concentrates most of the differences between supertypes, the B pocket showing a particularly high level of variation. Moreover, at HLA-B, the reassignment of alleles into random groups does not reproduce the patterns of population differentiation observed with supertypes. We thus conclude that differently from HLA-A, for which supertype and allelic variation show similar patterns of nucleotide diversity within and between populations, HLA-B has likely evolved through specific adaptations of its B pocket to local pathogens.

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The simultaneous typing of five-HLA loci at high resolution and the availability of pedigree data allowed us to characterize extended five-locus phased haplotypes in 124 Nigerian families and to compare the observed frequencies with those expected by an expectation-maximization algorithm for unphased data. Despite the occurrence of some frequent alleles at each locus (e.g. B*53:01, which is assumed to protect against Plasmodium falciparum), as many as 82% of the sampled individuals carry two unique five-locus haplotypes and only three extended haplotypes with frequency above 1% exhibit significant linkage disequilibrium. Although preliminary, these results reveal an extreme level of HLA diversity in the Nigerian population, which reflects both its multi-ethnic composition and the very ancient demographic history of African populations.

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Systematic analyses of human leukocyte antigen (HLA) profiles in different populations may increase the efficiency of bone marrow donor selection and help reconstructing human peopling history. We typed HLA-A, -B, and -DRB1 allele groups in two bone marrow donor cohorts of 2402 Hungarians and 186 Hungarian Gypsies and compared them with several Central-European, Spanish Gypsy, and Indian populations. Our results indicate that different European Gypsy populations share a common origin but diverged genetically as a consequence of founder effect and rapid genetic drift, whereas other European populations are related genetically in relation to geography. This study also suggests that while HLA-A accurately depicts the effects of genetic drift, HLA-B, and -DRB1 conserve more signatures of ancient population relationships, as a result of balancing selection.

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[This corrects the article DOI: 10.4137/EBO.S33488.].

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SELECTOR is a software package for studying the evolution of multiallelic genes under balancing or positive selection while simulating complex evolutionary scenarios that integrate demographic growth and migration in a spatially explicit population framework. Parameters can be varied both in space and time to account for geographical, environmental, and cultural heterogeneity. SELECTOR can be used within an approximate Bayesian computation estimation framework. We first describe the principles of SELECTOR and validate the algorithms by comparing its outputs for simple models with theoretical expectations. Then, we show how it can be used to investigate genetic differentiation of loci under balancing selection in interconnected demes with spatially heterogeneous gene flow. We identify situations in which balancing selection reduces genetic differentiation between population groups compared with neutrality and explain conflicting outcomes observed for human leukocyte antigen loci. These results and three previously published applications demonstrate that SELECTOR is efficient and robust for building insight into human settlement history and evolution.

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Next generation sequencing (NGS) is currently being adapted by different biotechnological platforms to the standard typing method for HLA polymorphism, the huge diversity of which makes this initiative particularly challenging. Boosting the molecular characterization of the HLA genes through efficient, rapid, and low-cost technologies is expected to amplify the success of tissue transplantation by enabling us to find donor-recipient matching for rare phenotypes. But the application of NGS technologies to the molecular mapping of the MHC region also anticipates essential changes in population genetic studies. Huge amounts of HLA sequence data will be available in the next years for different populations, with the potential to change our understanding of HLA variation in humans. In this review, we first explain how HLA sequencing allows a better assessment of the HLA diversity in human populations, taking also into account the methodological difficulties it introduces at the statistical level; secondly, we show how analyzing HLA sequence variation may improve our comprehension of population genetic relationships by facilitating the identification of demographic events that marked human evolution; finally, we discuss the interest of both HLA and genome-wide sequencing and genotyping in detecting functionally significant SNPs in the MHC region, the latter having also contributed to the makeup of the HLA molecular diversity observed today.

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Genetic differences between Northeast Asian (NEA) and Southeast Asian (SEA) populations have been observed in numerous studies. At the among-population level, despite a clear north-south differentiation observed for many genetic markers, debates were led between abrupt differences and a continuous pattern. At the within-population level, whether NEA or SEA populations have higher genetic diversity is also highly controversial. In this study, we analyzed a large set of HLA data from East Asia in order to map the genetic variation among and within populations in this continent and to clarify the distribution pattern of HLA lineages and alleles. We observed a genetic differentiation between NEA and SEA populations following a continuous pattern from north to south, and we show a significant and continuous decrease of HLA diversity by the same direction. This continuity is shaped by clinal distributions of many HLA lineages and alleles with increasing or decreasing frequencies along the latitude. These results bring new evidence in favor of the "overlapping model" proposed previously for East Asian peopling history, whereby modern humans migrated eastward from western Eurasia via two independent routes along each side of the Himalayas and, later, overlapped in East Asia across open land areas. Our study strongly suggests that intensive gene flow between NEA and SEA populations occurred and shaped the latitude-related continuous pattern of genetic variation and the peculiar HLA lineage and allele distributions observed in this continent. Probably for a very long period, the exact duration of these events remains to be estimated.

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The prevalence of rheumatoid arthritis and its specific autoantibodies varies in different populations. This variability depends on the genetic polymorphism of the immune response genes among which the HLA system plays a major role. In this context, we studied the HLA-DRB1 and HLA-DQB1 first-level allele frequencies in 100 Albanian patients with rheumatoid arthritis (RA), and taking into account their rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA) serologic subgroups, we compared them with the respective frequencies in a population of 191 Albanian individuals without known pathology. No differences were found between the controls and the RA patient group as a whole, but three statistically significant differences were found: an increase in DRB1*04 among ACPA+, RF+ and ACPA+/RF+ patients, a significant decrease in DRB1*11 among ACPA+/RF+ and also a decrease in DRB1*13 among RF+ patient subgroups. Comparing allele frequencies of putatively associated RA alleles in different European populations revealed a significant negative correlation between the RA predisposing DRB1*04 and protective DRB1*11 allele frequencies. A statistically significant correlation was also found between RA prevalence rates and DRB1*04 as well as DRB1*11 frequencies. The relatively low frequencies of DRB1*04 and high DRB1*11 in the Albanian population might explain the rather low positivity rate of ACPA and RF antibodies among the Albanian RA patients. These specific association patterns suggest that this first study of RA in an Albanian population should be followed up to include second level or higher definition of HLA alleles and to compare RA patterns among European populations.

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Explaining the genetic diversity of past and present European populations Although it is the continent with the lowest genomic diversity, Europe embraces a significant degree of variation, shaped by complex demographic events and locus-specific selective factors linked to environmental conditions. The European genetic diversity observed today has also important clinical and epidemiological implications. Different questions related to these topics are addressed in this special topic issue of eight excellent papers written by specialized European teams. The papers document the remarkable progress achieved in the last years in exploring human genomic diversity, both in past and present populations, in reconstructing complex scenarios of European peopling history using sophisticated data analyses and computer simulations, in identifying signatures of adaptive selection in milk digestion- and immune-related genes, and in applying this knowledge to crucial health issues, from tissue transplantation to disease associations. Genetic Diversity in European Populations: Evolutionary Evidence and Medical Implications is of special interest to researchers and students in biological and medical sciences and clinicians, who wish to update their knowledge in the field of European genetic diversity for basic research and medical applications.

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The Major Histocompatibility Complex Class I Chain-Related Gene A (MICA) is located 46.4 Kb centromeric to HLA-B locus on chromosome 6; 84 alleles have been described so far. To assess the distribution of MICA alleles in an Austrian population, 322 unrelated Austrian blood donors have been typed for MICA by direct sequencing of amplified exons 2-5; sequencing of exon 6 and separating alleles by haplotype specific primers or by cloning was performed to resolve ambiguities. HLA-B was typed at low level resolution and linkage disequilibrium was determined. We observed 20 already known and four novel MICA alleles. MICA*008:01/04 was the most frequent allele (42%), followed by MICA*002:01 (11%) and MICA*009:01 (9%), three alleles (MICA*029, *067 and *068) were observed only once. No deviation from the Hardy Weinberg equilibrium was observed. Linkage disequilibrium between MICA and HLA-B alleles was observed, most extensively between MICA*008:01/04 and HLA-B*07. Our population data are in agreement with other European populations. The fact that four novel alleles have been observed indicates that the polymorphism of MICA is larger than currently estimated.

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The Mamu-A, Mamu-B, and Mamu-DRB genes of the rhesus macaque show several levels of complexity such as allelic heterogeneity (polymorphism), copy number variation, differential segregation of genes/alleles present on a haplotype (diversity) and transcription level differences. A combination of techniques was implemented to screen a large panel of pedigreed Indian rhesus macaques (1,384 individuals representing the offspring of 137 founding animals) for haplotype diversity in an efficient and inexpensive manner. This approach allowed the definition of 140 haplotypes that display a relatively low degree of region variation as reflected by the presence of only 17 A, 18 B and 22 DRB types, respectively, exhibiting a global linkage disequilibrium comparable to that in humans. This finding contrasts with the situation observed in rhesus macaques from other geographic origins and in cynomolgus monkeys from Indonesia. In these latter populations, nearly every haplotype appears to be characterised by a unique A, B and DRB region. In the Indian population, however, a reshuffling of existing segments generated "new" haplotypes. Since the recombination frequency within the core MHC of the Indian rhesus macaques is relatively low, the various haplotypes were most probably produced by recombination events that accumulated over a long evolutionary time span. This idea is in accord with the notion that Indian rhesus macaques experienced a severe reduction in population during the Pleistocene due to a bottleneck caused by geographic changes. Thus, recombination-like processes appear to be a way to expand a diminished genetic repertoire in an isolated and relatively small founder population.

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In this article, we first present four significant cases where human leukocyte antigen (HLA) studies have been useful for the reconstruction of human peopling history on the worldwide scale; i.e., the spread of modern humans from East Africa, the colonization of East Asia along two geographic routes, the co-evolution of genes and languages in Africa, and the peopling of Europe through a main northward migration. These examples show that natural selection did not erase the genetic signatures of our past migrations in the HLA genetic diversity patterns observed today. In the second part, we summarize our studies on Easter Island. Using genomic HLA typing, we could trace an introduction of HLA alleles of native American (Amerindian) origin to Easter Island before the Peruvian slave trades; i.e., before the 1860s, and provide suggestive evidence that they may have already been introduced in prehistoric time. Our results give further support to an initial Polynesian population of the island, but also reveal an early contribution by Amerindians. Together, our data illustrate the usefulness of typing for HLA alleles to complement genetic analyses in anthropological investigations.

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HLA genes are highly polymorphic in human populations as a result of diversifying selection related to their immune function. However, HLA geographic variation worldwide suggests that demographic factors also shaped their evolution. We here analyzed in detail HLA genetic variation in Europe in order to identify signatures of migration history and/or natural selection.

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This study aims at investigating the HLA molecular variation across Switzerland in order to determine possible regional differences, which would be highly relevant to several purposes: optimizing donor recruitment strategies in hematopoietic stem cell transplantation (HSCT), providing reliable reference data in HLA and disease association studies, and understanding the population genetic background(s) of this culturally heterogeneous country. HLA molecular data of more than 20,000 HSCT donors from 9-13 recruitment centers of the whole country were analyzed. Allele and haplotype frequencies were estimated by using new computer tools adapted to the heterogeneity and ambiguity of the data. Non-parametric and resampling statistical tests were performed to assess Hardy-Weinberg equilibrium, selective neutrality and linkage disequilibrium among different loci, both in each recruitment center and in the whole national registry. Genetic variation was explored through genetic distance and hierarchical analysis of variance taking into account both geographic and linguistic subdivisions in Switzerland. The results indicate a heterogeneous genetic makeup of the Swiss population: first, allele frequencies estimated on the whole national registry strongly deviate from Hardy-Weinberg equilibrium, by contrast with the results obtained for individual centers; second, a pronounced differentiation is observed for Ticino, Graubünden, and, to a lesser extent, Wallis, suggesting that the Alps represent(ed) a barrier to gene flow; finally, although cultural (linguistic) boundaries do not represent a main genetic differentiation factor in Switzerland, the genetic relatedness between population from south-eastern Switzerland and Italy agrees with historical and linguistic data. Overall, this study justifies the maintenance of a decentralized donor recruitment structure in Switzerland allowing increasing the genetic diversity of the national--and hence global--donor registry. It also indicates that HLA data of local donor recruitment centers can be used as reference data in both epidemiological and population genetic studies focusing on the genetic history of present European populations.

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Human leucocyte antigen (HLA) loci have a complex evolution where both stochastic (e.g. genetic drift) and deterministic (natural selection) forces are involved. Owing to their extraordinary level of polymorphism, HLA genes are useful markers for reconstructing human settlement history. However, HLA variation often deviates significantly from neutral expectations towards an excess of genetic diversity. Because HLA molecules play a crucial role in immunity, this observation is generally explained by pathogen-driven-balancing selection (PDBS). In this study, we investigate the PDBS model by analysing HLA allelic diversity on a large database of 535 populations in relation to pathogen richness. Our results confirm that geographical distances are excellent predictors of HLA genetic differentiation worldwide. We also find a significant positive correlation between genetic diversity and pathogen richness at two HLA class I loci (HLA-A and -B), as predicted by PDBS, and a significant negative correlation at one HLA class II locus (HLA-DQB1). Although these effects are weak, as shown by a loss of significance when populations submitted to rapid genetic drift are removed from the analysis, the inverse relationship between genetic diversity and pathogen richness at different loci indicates that HLA genes have adopted distinct evolutionary strategies to provide immune protection in pathogen-rich environments.

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The development of molecular typing techniques applied to the study of population genetic diversity originates data with increasing precision but at the cost of some ambiguities. As distinct techniques may produce distinct kinds of ambiguities, a crucial issue is to assess the differences between frequency distributions estimated from data produced by alternative techniques for the same sample. To that aim, we developed a resampling scheme that allows evaluating, by statistical means, the significance of the difference between two frequency distributions. The same approach is then shown to be applicable to test selective neutrality when only sample frequencies are known. The use of these original methods is presented here through an application to the genetic study of a Munda human population sample, where three different HLA loci were typed using two different molecular methods (reverse PCR-SSO typing on microbeads arrays based on Luminex technology and PCR-SSP typing), as described in details in the companion article by Riccio et al. [The Austroasiatic Munda population from India and its enigmatic origin: An HLA diversity study. Hum. Biol. 38:405-435 (2011)]. The differences between the frequency estimates of the two typing techniques were found to be smaller than those resulting from sampling. Overall, we show that using a resampling scheme in validating frequency estimates is effective when alternative frequency estimates are available. Moreover, resampling appears to be the unique way to test selective neutrality when only frequency data are available to describe the genetic structure of populations.

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The Austroasiatic linguistic family disputes its origin between two geographically distant regions of Asia, India, and Southeast Asia, respectively. As genetic studies based on classical and gender-specific genetic markers provided contradictory results to this debate thus far, we investigated the HLA diversity (HLA-A, -B, and -DRB1 loci) of an Austroasiatic Munda population from Northeast India and its relationships with other populations from India and Southeast Asia. Because molecular methods currently used to test HLA markers often provide ambiguous results due to the high complexity of this polymorphism, we applied two different techniques (reverse PCR-SSO typing on microbeads arrays based on Luminex technology, and PCR-SSP typing) to type the samples. After validating the resulting frequency distributions through the original statistical method described in our companion article ( Nunes et al. 2011 ), we compared the HLA genetic profile of the sampled Munda to those of other Asiatic populations, among which Dravidian and Indo-European-speakers from India and populations from East and Southeast Asia speaking languages belonging to different linguistic families. We showed that the Munda from Northeast India exhibit a peculiar genetic profile with a reduced level of HLA diversity compared to surrounding Indian populations. They also exhibit less diversity than Southeast Asian populations except at locus DRB1. Several analyses using genetic distances indicate that the Munda are much more closely related to populations from the Indian subcontinent than to Southeast Asian populations speaking languages of the same Austroasiatic linguistic family. On the other hand, they do not share a closer relationship with Dravidians compared with Indo-Europeans, thus arguing against the idea that the Munda share a common and ancient Indian origin with Dravidians. Our results do not favor either a scenario where the Munda would be representative of an ancestral Austroasiatic population giving rise to an eastward Austroasiatic expansion to Southeast Asia. Rather, their peculiar genetic profile is better explained by a decrease in genetic diversity through genetic drift from an ancestral population having a genetic profile similar to present-day Austroasiatic populations from Southeast Asia (thus suggesting a possible southeastern origin), followed by intensive gene flow with neighboring Indian populations. This conclusion is in agreement with archaeological and linguistic information. The history of the Austroasiatic family represents a fascinating example where complex interactions among culturally distinct human populations occurred in the past.

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The peopling of East Asia by the first modern humans is strongly debated from a genetic point of view. A north-south genetic differentiation observed in this geographic area suggests different hypotheses on the origin of Northern East Asian (NEA) and Southern East Asian (SEA) populations. In this study, the highly polymorphic HLA markers were used to investigate East Asian genetic diversity. Our database covers a total of about 127,000 individuals belonging to 84 distinct Asian populations tested for HLA-A, -B, -C, -DPB1, and/or -DRB1 alleles. Many Chinese populations are represented, which have been sampled in the last 30 years but rarely taken into account in international research due to their data published in Chinese. By using different statistical methods, we found a significant correlation between genetics and geography and relevant genetic clines in East Asia. Additionally, HLA alleles appear to be unevenly distributed: some alleles observed in NEA populations are widespread at the global level, while some alleles observed in SEA populations are virtually unique in Asia. The HLA genetic variation in East Asia is also characterized by a decrease of diversity from north to south, although a reverse pattern appears when one only focuses on alleles restricted to Asia. These results reflect a more complex migration history than that illustrated by the "southern-origin" hypothesis, as genetic contribution of ancient human migrations through a northern route has probably been quite substantial. We thus suggest a new overlapping model where northward and southward opposite migrations occurring at different periods overlapped.

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The genes coding for the main molecules involved in the human immune system--immunoglobulins, human leucocyte antigen (HLA) molecules and killer-cell immunoglobulin-like receptors (KIR)--exhibit a very high level of polymorphism that reveals remarkable frequency variation in human populations. 'Genetic marker' (GM) allotypes located in the constant domains of IgG antibodies have been studied for over 40 years through serological typing, leading to the identification of a variety of GM haplotypes whose frequencies vary sharply from one geographic region to another. An impressive diversity of HLA alleles, which results in amino acid substitutions located in the antigen-binding region of HLA molecules, also varies greatly among populations. The KIR differ between individuals according to both gene content and allelic variation, and also display considerable population diversity. Whereas the molecular evolution of these polymorphisms has most likely been subject to natural selection, principally driven by host-pathogen interactions, their patterns of genetic variation worldwide show significant signals of human geographic expansion, demographic history and cultural diversification. As current developments in population genetic analysis and computer simulation improve our ability to discriminate among different--either stochastic or deterministic--forces acting on the genetic evolution of human populations, the study of these systems shows great promise for investigating both the peopling history of modern humans in the time since their common origin and human adaptation to past environmental (e.g. pathogenic) changes. Therefore, in addition to mitochondrial DNA, Y-chromosome, microsatellites, single nucleotide polymorphisms and other markers, immunogenetic polymorphisms represent essential and complementary tools for anthropological studies.

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Molecular differences between HLA alleles vary up to 57 nucleotides within the peptide binding coding region of human Major Histocompatibility Complex (MHC) genes, but it is still unclear whether this variation results from a stochastic process or from selective constraints related to functional differences among HLA molecules. Although HLA alleles are generally treated as equidistant molecular units in population genetic studies, DNA sequence diversity among populations is also crucial to interpret the observed HLA polymorphism. In this study, we used a large dataset of 2,062 DNA sequences defined for the different HLA alleles to analyze nucleotide diversity of seven HLA genes in 23,500 individuals of about 200 populations spread worldwide. We first analyzed the HLA molecular structure and diversity of these populations in relation to geographic variation and we further investigated possible departures from selective neutrality through Tajima's tests and mismatch distributions. All results were compared to those obtained by classical approaches applied to HLA allele frequencies.Our study shows that the global patterns of HLA nucleotide diversity among populations are significantly correlated to geography, although in some specific cases the molecular information reveals unexpected genetic relationships. At all loci except HLA-DPB1, populations have accumulated a high proportion of very divergent alleles, suggesting an advantage of heterozygotes expressing molecularly distant HLA molecules (asymmetric overdominant selection model). However, both different intensities of selection and unequal levels of gene conversion may explain the heterogeneous mismatch distributions observed among the loci. Also, distinctive patterns of sequence divergence observed at the HLA-DPB1 locus suggest current neutrality but old selective pressures on this gene. We conclude that HLA DNA sequences advantageously complement HLA allele frequencies as a source of data used to explore the genetic history of human populations, and that their analysis allows a more thorough investigation of human MHC molecular evolution.

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The Strait of Gibraltar is a crucial area in the settlement history of modern humans because it represents a possible connection between Africa and Europe. So far, genetic data were inconclusive about the fact that this strait constitutes a barrier to gene flow, as previous results were highly variable depending on the genetic locus studied. The present study evaluates the impact of the Gibraltar region in reducing gene flow between populations from North-Western Africa and South-Western Europe, by comparing formally various genetic loci. First, we compute several statistics of population differentiation. Then, we use an original simulation approach in order to infer the most probable evolutionary scenario for the settlement of the area, taking into account the effects of both demography and natural selection at some loci.

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In this study, the HLA-DRB1 and -DQB1 molecular diversity of two Berber-speaking populations of Southern Tunisia was analysed. Genetic comparisons indicate that both populations exhibit peculiar profiles for HLA-DRB1, as they diverge significantly from most other North Africans, while being highly diversified. At the opposite, they are much less differentiated from neighbouring populations according to the HLA-DQB1 polymorphism. Overall, the HLA class II genetic structure of Arab and Berber-speaking populations from Tunisia, and of North Africa as a whole, is complex and cannot be simply explained by geographic or linguistic differentiations. The present North African genetic pool has probably been shaped by both genetic drift and the contribution of genetically heterogeneous populations during the history of settlement of North Africa.

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The Noir Marron communities are the direct descendants of African slaves brought to the Guianas during the four centuries (16th to 19th) of the Atlantic slave trade. Among them, three major ethnic groups have been studied: the Aluku, the Ndjuka and the Saramaka. Their history led them to share close relationships with Europeans and Amerindians, as largely documented in their cultural records. The study of Gm polymorphisms of immunoglobulins may help to estimate the amount of gene flow linked to these cultural exchanges. Surprisingly, very low levels of European contribution (2.6%) and Amerindian contribution (1.7%) are detected in the Noir Marron gene pool. On the other hand, an African contribution of 95.7% redraws their origin to West Africa (F(ST) < or = 0.15). This highly preserved African gene pool of the Noir Marron is unique in comparison to other African American populations of Latin America, who are notably more admixed.

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The Afro-Asiatic and Nilo-Saharan language families come into contact in Western Ethiopia. Ethnic diversity is particularly high in the South, where the Nilo-Saharan Nyangatom and the Afro-Asiatic Daasanach dwell. Despite their linguistic differentiation, both populations rely on a similar agripastoralist mode of subsistence. Analysis of mitochondrial DNA extracted from Nyangatom and Daasanach archival sera revealed high levels of diversity, with most sequences belonging to the L haplogroups, the basal branches of the mitochondrial phylogeny. However, in sharp contrast with other Ethiopian populations, only 5% of the Nyangatom and Daasanach sequences belong to haplogroups M and N. The Nyangatom and Daasanach were found to be significantly differentiated, while each of them displays close affinities with some Tanzanian populations. The strong genetic structure found over East Africa was neither associated with geography nor with language, a result confirmed by the analysis of 6711 HVS-I sequences of 136 populations mainly from Africa. Processes of migration, language shift and group absorption are documented by linguists and ethnographers for the Nyangatom and Daasanach, thus pointing to the probably transient and plastic nature of these ethnic groups. These processes, associated with periods of isolation, could explain the high diversity and strong genetic structure found in East Africa.

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The lactase enzyme allows lactose digestion in fresh milk. Its activity strongly decreases after the weaning phase in most humans, but persists at a high frequency in Europe and some nomadic populations. Two hypotheses are usually proposed to explain the particular distribution of the lactase persistence phenotype. The gene-culture coevolution hypothesis supposes a nutritional advantage of lactose digestion in pastoral populations. The calcium assimilation hypothesis suggests that carriers of the lactase persistence allele(s) (LCT*P) are favoured in high-latitude regions, where sunshine is insufficient to allow accurate vitamin-D synthesis. In this work, we test the validity of these two hypotheses on a large worldwide dataset of lactase persistence frequencies by using several complementary approaches.

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This paper presents a meta-analysis of high-resolution human leukocyte antigen (HLA) allele frequency data describing 497 population samples. Most of the datasets were compiled from studies published in eight journals from 1990 to 2007; additional datasets came from the International Histocompatibility Workshops and from the AlleleFrequencies.net database. In all, these data represent approximately 66,800 individuals from throughout the world, providing an opportunity to observe trends that may not have been evident at the time the data were originally analyzed, especially with regard to the relative importance of balancing selection among the HLA loci. Population genetic measures of allele frequency distributions were summarized across populations by locus and geographic region. A role for balancing selection maintaining much of HLA variation was confirmed. Further, the breadth of this meta-analysis allowed the ranking of the HLA loci, with DQA1 and HLA-C showing the strongest balancing selection and DPB1 being compatible with neutrality. Comparisons of the allelic spectra reported by studies since 1990 indicate that most of the HLA alleles identified since 2000 are very-low-frequency alleles. The literature-based allele-count data, as well as maps summarizing the geographic distributions for each allele, are available online.

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In this study, we estimate the amount of human leukocyte antigen (HLA) genetic diversity in the global human population at three levels of population hierarchy: within populations; among populations within continents and among continents on large sets of HLA population data gathered during the last international histocompatibility and immunogenetics workshops and conferences. The results indicate that loci HLA-A, B, C, DRB1, DQA1 and DQB1 exhibit a higher amount of diversity among individuals of the same population than observed for neutral polymorphisms (average diversity of 90.3% compared with 84.4%-87.6% for neutral DNA markers). On the other hand, the value (84%) obtained for HLA-DPB1 is very similar to those observed for non-HLA nuclear markers, in agreement with other results suggesting the neutrality of this locus. In addition to the results of the hierarchical analysis of variance, selective neutrality tests indicate that loci B, C and DRB1 are the most affected by balancing selection. However, one cannot discriminate between a direct selective effect acting on those loci or a general effect of associative overdominance acting over the large HLA region (in linkage disequilibrium) encompassing those loci.

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The GM polymorphism of human immunoglobulins is analyzed in three Berber populations of southern Tunisia and compared to other GM data. Genetic diversity among Tunisian populations is higher than that among Europeans but does not exhibit any significant geographic or linguistic structure. This result suggests a complex pattern of genetic differentiation.

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This study investigates the GM genetic relationships of 82 human populations, among which 10 represent original data, within and among the main broad geographic areas of the world. Different approaches are used: multidimensional scaling analysis and test for isolation by distance, to assess the correlation between genetic variation and spatial distributions; analysis of variance, to investigate the genetic structure at different hierarchical levels of population subdivision; genetic similarity map (geographic map distorted by available genetic information), to identify regions of high and low genetic variation; and minimal spanning network, to point out possible migration routes across continental areas. The results show that the GM polymorphism is characterized by one of the highest amounts of genetic variation observed so far among populations of different continents (Fct=0.3915, P < 0.0001). GM diversity can be explained by a model of isolation by distance (IBD) at most continental levels, with a particularly significant fit to IBD for the Middle East and Europe. Five peripheral regions of the world (Europe, west and south sub-Saharan Africa, Southeast Asia, and America) exhibit a low level of genetic diversity both within and among populations. By contrast, East and North African, Southwest Asian, and Northeast Asian populations are highly diverse and interconnected genetically by large genetic distances. Therefore, the observed GM variation can be explained by a "centrifugal model" of modern humans peopling history, involving ancient dispersals across a large intercontinental area spanning from East Africa to Northeast Asia, followed by recent migrations in peripheral geographic regions.

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Ten population samples from different geographic origins were tested serologically for the AG polymorphism of human beta-lipoproteins. Their haplotype frequencies were used with previously published data to perform a wide analysis of AG genetic differentiations throughout the world. Coancestry coefficients were computed from weighted F(ST)s among populations by using a matrix of molecular distances among AG haplotypes, which is here determined on the basis of DNA studies. Coancestry coefficients derived from unweighted F(ST)s and more classical Prevosti distances were computed on the same data and used for a comparison. In all cases a highly significant correlation was found between genetics and geography on a worldwide scale, while the significance of the correlation with linguistics differed. A test of significance of the pairwise F(ST)s among populations also gave different results depending on whether the molecular distance matrix among AG haplotypes was included. Globally, this study shows that in spite of being highly significantly correlated to each other, different genetic distance measures can lead to different interpretations of the same data set. Moreover, the elucidation of the molecular models related to the presently known serological polymorphisms may represent an additional tool for analyzing such polymorphisms in human population genetics studies.

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This study investigates the influence of different evolutionary factors on the patterns of human leukocyte antigen (HLA) genetic diversity within sub-Saharan Africa, and between Africa, Europe, and East Asia. This is done by comparing the significance of several statistics computed on equivalent population data sets tested for two HLA class II loci, DRB1 and DPB1, which strongly differ from each other by the shape of their allelic distributions. Similar results are found for the two loci concerning highly significant correlations between geographic and genetic distances at the world scale, high levels of genetic diversity within sub-Saharan Africa and East Asia, and low within Europe, and low genetic differentiations among the three broad continental areas, with no special divergence of Africa. On the other hand, DPB1 behaves as a neutral polymorphism, although a significant excess of heterozygotes is often observed for DRB1. Whereas the pattern observed for DPB1 is explained by geographic differentiations and genetic drift in isolated populations, balancing selection is likely to have prevented genetic differentiations among populations at the DRB1 locus. However, this selective effect did not disrupt the high correlation found between DRB1 and geography at the world scale, nor between DRB1 and linguistic differentiations at the African level.

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HLA-Cw alleles were determined by high-resolution polymerase chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) oligotyping in a sample of 165 Mandenka, a population from Eastern Senegal previously analysed for A/B and DRB/DQB polymorphisms. A total of 18 Cw alleles were identified, with Cw*0401/5 and 1601 accounting for a combined frequency of 36%. A comparison of Cw allele frequencies among several populations of different origins, Mandenka, Swiss, English, Ashkenazi Jews from the UK and Japanese, reveals a high genetic heterogeneity among them, but also a much closer relationship between Mandenka, Europeans and Ashkenazi than between any of these populations and Japanese. Cw*0501, Cw*0701 and Cw*1601, among others, appear to be restricted to the European and African populations. Many B-Cw haplotypes exhibit a significant linkage disequilibrium in the Mandenka, among which B*3501-Cw*0401 and B*7801-Cw*1601, formed by the most frequent B and Cw alleles, and B*5201-Cw*1601, B*5702-Cw*18 and B*4410-Cw*0401, not yet observed in other populations. B*3501-Cw*0401 is found with similar frequencies in Europeans. The results possibly support a close historical relationship between Africans and Europeans as compared to East Asiatics. However, the HLA-Cw frequency distributions are characterised by an excess of heterozygotes, indicating that balancing selection may have played a role in the evolution of this polymorphism.

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A sample of 100 individuals from 50 French families of known pedigrees were typed for 14 loci of the HLA region (DPB1, DQB1, DQA1, DRB1, DRB3, 4, 5, C4B, C4A, Bf, C2, TNFa, TNFb, B, Cw, A). Linkage disequilibrium in each pair of loci was investigated by an exact test using a Markov chain algorithm. The results indicate no disequilibrium between DPB1 and the other loci, whereas the other class II genes are all significantly linked to each other. Linkage disequilibrium is also detected between some pairs of class I and class II-class I loci despite the long physical distance separating the loci (e.g. A-B, Cw-DRB1). On the other hand, some contiguous loci of the class III region are found to be in equilibrium with each other. Several hypotheses including selection, but also unequal allelic diversity at different MHC loci are discussed to explain this complex pattern of linkage disequilibrium.

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