staff

Stéphane Buhler

External collaborator in Anthropology & Immunogenetics

  • T: +41 22 379 69 64
  • office 4-414 (Sciences II)
  • The HLA-B landscape of Africa: signatures of pathogen-driven selection and molecular identification of candidate alleles to malaria protection. Mol. Ecol. 2017 Sep;():. 10.1111/mec.14366.

    abstract

    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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  • Common and well-documented HLA alleles over all of Europe and within European sub-regions: A catalogue from the European Federation for Immunogenetics. HLA 2017 Feb;89(2):104-113. 10.1111/tan.12956.

    abstract

    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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  • The HLA-A, -B and -DRB1 polymorphism in a large dataset of South Brazil bone marrow donors from Rio Grande do Sul. HLA 2016 Dec;():. 10.1111/tan.12933.

    abstract

    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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  • Mapping the HLA diversity of the Iberian Peninsula. Hum. Immunol. 2016 Jul;():. S0198-8859(16)30153-7. 10.1016/j.humimm.2016.06.023.

    abstract

    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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  • HLA class I molecular variation and peptide-binding properties suggest a model of joint divergent asymmetric selection. Immunogenetics 2016 Jul;68(6-7):401-16. 10.1007/s00251-016-0918-x. 10.1007/s00251-016-0918-x. PMC4911380.

    abstract

    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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  • KIR genotypic diversity in Portuguese and analysis of KIR gene allocation after allogeneic hematopoietic stem cell transplantation. HLA 2016 May;87(5):375-80. 10.1111/tan.12795.

    abstract

    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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  • HLA supertype variation across populations: new insights into the role of natural selection in the evolution of HLA-A and HLA-B polymorphisms. Immunogenetics 2015 Nov;67(11-12):651-63. 10.1007/s00251-015-0875-9. 10.1007/s00251-015-0875-9. PMC4636516.

    abstract

    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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  • HLA genetic diversity in Hungarians and Hungarian Gypsies: complementary differentiation patterns and demographic signals revealed by HLA-A, -B and -DRB1 in Central Europe. Tissue Antigens 2015 Aug;86(2):115-21. 10.1111/tan.12600.

    abstract

    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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  • HLA-A, B and DRB1 genetic heterogeneity in Quebec. Int. J. Immunogenet. 2015 Apr;42(2):69-77. 10.1111/iji.12177.

    abstract

    Recent studies have shown that under specific conditions such as high sample sizes and Hardy-Weinberg equilibrium, bone marrow donor registry data can be used to describe HLA molecular variation across a specific geographic area, thus providing excellent data sets to infer human migrations history. The province of Quebec is known to have experienced a complex history of settlement, characterized by multiple migrations and demographic changes. We thus analysed the data of more than 13 000 unrelated individuals acting as volunteer bone marrow donors who were molecularly typed for HLA-A, B and DRB1 polymorphisms in the Héma-Quebec registry. HLA allelic and haplotypic frequencies were estimated and compared among regions. The results indicate that, despite an overall low genetic diversity in Quebec, genetic variation is correlated with geography, compatible with isolation-by-distance across the province. However, some localities also harbour contrasting genetic profiles, that is a highly diversified genetic pool in the two main urban centres (Montréal and Laval) and a more pronounced genetic divergence of two specific regions characterized by a peculiar peopling history (Saguenay-Lac-St-Jean and Gaspésie-Îles-De-La-Madeleine). In agreement with other independent molecular markers, the observations based on HLA data thus account for the main demographic mechanisms that shaped the genetic structure of the present day Quebecer population. In addition, the detailed analysis of the Héma-Quebec registry provides key genetic information on which an efficient bone marrow transplantation recruitment strategy can be settled.

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  • A new HLA map of Europe: Regional genetic variation and its implication for peopling history, disease-association studies and tissue transplantation. Hum. Hered. 2013 ;76(3-4):162-77. 000360855. 10.1159/000360855.

    abstract

    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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  • The heterogeneous HLA genetic makeup of the Swiss population. PLoS ONE 2012 ;7(7):e41400. 10.1371/journal.pone.0041400. PONE-D-12-01163. PMC3405111.

    abstract

    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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  • Immunogenetics as a tool in anthropological studies. Immunology 2011 Jun;133(2):143-64. 10.1111/j.1365-2567.2011.03438.x. PMC3088978.

    abstract

    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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  • HLA DNA sequence variation among human populations: molecular signatures of demographic and selective events. PLoS ONE 2011 ;6(2):e14643. 10.1371/journal.pone.0014643. PMC3051395.

    abstract

    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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  • HLA-C molecular characterization of a Lebanese population and genetic structure of 39 populations from Europe to India-Pakistan. Tissue Antigens 2006 Jul;68(1):44-57. TAN621. 10.1111/j.1399-0039.2006.00621.x.

    abstract

    Lebanon is located at a continental crossroad between Europe, Africa, and Asia. This region has been the center of wide-scale movements of populations as well as the theater of genetic and cultural trade off among neighboring populations. In this study, HLA-C alleles were characterized by a PCR-SSOP (sequence-specific oligonucleotide probes) hybridization protocol in a sample of 97 Lebanese. A total of 23 alleles were identified with four predominant, Cw*0401, Cw*0602, Cw*0701/06, and Cw*1203, accounting for almost 60% of HLA-C allele frequencies. We included the Lebanese data into a broad analysis of the HLA-C genetic structure of a large set of populations located in Europe, the Middle East, and the Indian subcontinent. Our results indicate that Lebanese exhibit an intermediate genetic profile among the populations from the Middle East, which constitute a rather homogeneous genetic group. In Europe, a high correlation coefficient is found between genetic and geographic distances. In this continent, we also identified a significant genetic frontier following a north-east to south-west axis. This frontier cuts through the Alps and the Pyrenees, thus separating the north-western European populations from those located in the eastern and Mediterranean areas. Finally, the populations from India - Pakistan are very heterogeneous, particularly the Dravidians. Their differentiation has probably been caused by rapid genetic drift under complex influences of cultural, linguistic, and/or religious barriers. Overall, the results show that the HLA-C genetic patterns of these three geographic regions, i.e., the Middle East, Europe, and India-Pakistan, have been shaped by very different genetic histories.

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  • PCR-SSOP molecular typing of HLA-C alleles in an Iranian population. Tissue Antigens 2002 Jun;59(6):525-30. tan590611.

    abstract

    HLA-C alleles were characterized by a polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) hybridization protocol in a sample of 120 Iranians from Tehran. A total of 23 alleles were identified with the four most predominant--Cw*0401, Cw*0602, Cw*1202, and Cw*0701/06--accounting for almost 50% of HLA-C alleles. A comparison of HLA-C diversity among several populations indicates that Iranians stand at an intermediate genetic position between Europeans and Africans, an observation that may be related to their geographical location at a continental crossroads. The results also reveal a very high correlation between genetic and geographic distances on a global scale. A total of 30 HLA-C-DRB1 haplotypes were found in the Iranians, with the highest frequencies of 6.6% and 6.04 % being for Cw*0602-DRB1*0701 and Cw*1202-DRB1*1502, respectively.

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