staff

Da Di

External collaborator in Anthropology & Immunogenetics

  • T: +41 22 379 69 64
  • office 4-414 (Sciences II)

  • Challenging Ancient DNA Results About Putative HLA Protection or Susceptibility to Yersinia pestis . Mol Biol Evol. 2022;39(4):msac073. doi:10.1093/molbev/msac073

    abstract

    In a recent article, Immel et al. (Immel A, Key FM, Szolek A, Barquera R, Robinson MK, Harrison GF, Palmer WH, Spyrou MA, Susat J, Krause-Kyora B, et al. 2021. Analysis of genomic DNA from medieval plague victims suggests long-term effect of Yersinia pestis on human immunity genes. Mol Biol Evol. 38:4059-4076) extracted DNA from 36 individuals dead from plague in Ellwangen, Southern Germany, during the 16th century. By comparing their human leukocyte antigen (HLA) genotypes with those of 50 present-day Ellwangen inhabitants, the authors reported a significant decrease of HLA-B*51:01 and HLA-C*06:02 and a significant increase of HLA-DRB1*13:01/13:02 frequencies from ancient to modern populations. After comparing these frequencies with a larger sample of 8,862 modern Germans and performing simulations of natural selection, they concluded that these changes had been driven by natural selection. In an attempt to provide more evidence on such stimulating results, we explored the HLA frequency patterns over all of Europe, we predicted binding affinities of HLA-B/C/DRB1 alleles to 106,515 Yersinia pestis-derived peptides, and we performed forward simulations of HLA genetic profiles under neutrality. Our analyses do not sustain the conclusions of HLA protection or susceptibility to plague based on ancient DNA.

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  • Like wings of a bird: functional divergence and complementarity between HLA-A and HLA-B molecules. Mol Biol Evol . 2021 Apr 13; 38(4):1580-1594. doi: 10.1093/molbev/msaa325

    abstract

    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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  • Binding affinities of 438 HLA proteins to complete proteomes of seven pandemic viruses and distributions of strongest and weakest HLA peptide binders in populations worldwide. HLA 2020 May;():. 10.1111/tan.13956.

    abstract

    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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  • 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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  • Computer simulation of human leukocyte antigen genes supports two main routes of colonization by human populations in East Asia. BMC Evol. Biol. 2015 ;15():240. 10.1186/s12862-015-0512-0. 10.1186/s12862-015-0512-0. PMC4632674.

    abstract

    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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  • Correction to: "Forward-in-Time, Spatially Explicit Modeling Software to Simulate Genetic Lineages Under Selection". Evol. Bioinform. Online 2015 ;11(Suppl 2):69. 10.4137/EBO.S39777. ebo-suppl.2-2015-069. PMC4939849.

    abstract

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

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  • Forward-in-Time, Spatially Explicit Modeling Software to Simulate Genetic Lineages Under Selection. Evol. Bioinform. Online 2015 ;11(Suppl 2):27-39. 10.4137/EBO.S33488. ebo-suppl.2-2015-027. PMC4768942.

    abstract

    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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  • HLA variation reveals genetic continuity rather than population group structure in East Asia. Immunogenetics 2014 Mar;66(3):153-60. 10.1007/s00251-014-0757-6.

    abstract

    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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  • Challenging views on the peopling history of East Asia: the story according to HLA markers. Am. J. Phys. Anthropol. 2011 May;145(1):81-96. 10.1002/ajpa.21470.

    abstract

    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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  • 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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