Pr Alicia Sanchez-Mazas

African populations remain underrepresented in studies of human genetic diversity, despite a growing interest in understanding how they have adapted to the diverse environments they live in. In particular, understanding the genetic basis of immune adaptation to pathogens is of paramount importance in a continent such as Africa, where the burden of infectious diseases is a major public health challenge. In this study, we investigated the molecular variation of four Human Leukocyte Antigens () class II genes (, , and ), directly involved in the immune response to parasitic infections, in more than 1000 individuals from 23 populations across North, East, Central and West Africa. By analyzing the molecular diversity of these populations in relation to various geographical, cultural and environmental factors, we identified divergent genetic profiles for several (semi-)nomadic populations of the Sahel belt as a signature of their unique demography. In addition, we observed significant genetic structuring supporting both substantial geographic and linguistic differentiations within West Africa. Furthermore, neutrality tests suggest balancing selection has been shaping the diversity of these four class II genes, which is consistent with molecular comparisons between genes and their orthologs in chimpanzees (). However, the most striking observation comes from linear modeling, demonstrating that the prevalence of , the primary pathogen of malaria in Africa, significantly explains a large proportion of the nucleotide diversity observed at the gene. , a highly frequent allele in Burkinabé populations, is identified as a potential protective allele against malaria, suggesting that strong pathogen-driven positive selection at this gene has shaped variation in Africa. Additionally, two low-frequency alleles, and also show significant associations with prevalence, supporting resistance to malaria is determined by multigenic and/or multiallelic combinations rather than single allele effects.

African populations remain underrepresented in studies of human genetic diversity, despite a growing interest in understanding how they have adapted to the diverse environments they live in. In particular, understanding the genetic basis of immune adaptation to pathogens is of paramount importance in a continent such as Africa, where the burden of infectious diseases is a major public health challenge. In this study, we investigated the molecular variation of four Human Leukocyte Antigens (HLA) class II genes (DRB1, DQA1, DQB1 and DPB1), directly involved in the immune response to parasitic infections, in more than 1000 individuals from 23 populations across North, East, Central and West Africa. By analyzing the HLA molecular diversity of these populations in relation to various geographical, cultural and environmental factors, we identified divergent genetic profiles for several (semi-)nomadic populations of the Sahel belt as a signature of their unique demography. In addition, we observed significant genetic structuring supporting both substantial geographic and linguistic differentiations within West Africa. Furthermore, neutrality tests suggest balancing selection has been shaping the diversity of these four HLA class II genes, which is consistent with molecular comparisons between HLA genes and their orthologs in chimpanzees (Patr). However, the most striking observation comes from linear modeling, demonstrating that the prevalence of Plasmodium falciparum, the primary pathogen of malaria in Africa, significantly explains a large proportion of the nucleotide diversity observed at the DPB1 gene. DPB1*01:01, a highly frequent allele in Burkinabé populations, is identified as a potential protective allele against malaria, suggesting that strong pathogen-driven positive selection at this gene has shaped HLA variation in Africa. Additionally, two low-frequency DRB1 alleles, DRB1*08:06 and DRB1*11:02, also show significant associations with P. falciparum prevalence, supporting resistance to malaria is determined by multigenic and/or multiallelic combinations rather than single allele effects.

A comprehensive knowledge of human leukocyte antigen (HLA) molecular variation worldwide is essential in human population genetics research and disease association studies and is also indispensable for clinical applications such as allogeneic hematopoietic cell transplantation, where ensuring HLA compatibility between donors and recipients is paramount. Enormous progress has been made in this field thanks to several decades of HLA population studies allowing the development of helpful databases and bioinformatics tools. However, it is still difficult to appraise the global HLA population diversity in a synthetic way. We thus introduce here a novel approach, based on approximately 2000 data sets, to assess this complexity by providing a fundamental synopsis of the most frequent HLA alleles observed in different regions of the world. This new knowledge will be useful not only as a fundamental reference for basic research, but also as an efficient guide for clinicians working in the field of transplantation.

As part of the worldwide effort to better characterize HLA diversity in populations, we have studied the population of Québec in Canada. This province has been defined by a complex history with multiple founder effects and migration patterns. We analyzed the typing data of 3806 individuals registered in Héma-Québec's Registry, which covered most administrative regions in Québec. Typing information was resolved at the second field level of resolution by next-generation sequencing (NGS) or by Sanger sequencing. We used the HLA-net.eu GENE[RATE] tools to estimate allele and two-locus haplotype frequencies for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1, as well as Hardy-Weinberg equilibrium (HWE), selective neutrality, and linkage disequilibrium. The chord genetic distance was also calculated between administrative regions and was visualized using non-metric multidimensional scaling (NMDS) analysis. While most individual regions were in HWE, HWE was rejected for the province considered as a whole. Some regions exhibited signatures of selection, mostly toward an excess of heterozygotes. Allele and haplotype frequencies revealed outlier regions that strongly differed from the other regions. NMDS plots also showed differences between regions. The administrative regions of the province of Québec displayed heterogeneity in their HLA profiles. This heterogeneity was attributable to differing allele and haplotype specificities by region. In particular, regions 02-Saguenay-Lac-Saint-Jean and 01-Bas-St-Laurent diverged from the rest of the regions. The urban regions 06-Montréal and 13-Laval were very diversified in their HLA profiles. Together, these results will help optimize donor recruitment strategies in Québec.

In biomedical research, population differences are of central interest. Variations in the frequency and severity of diseases and in treatment effects among human subpopulation groups are common in many medical conditions. Unfortunately, the practices in terms of subpopulation labeling do not exhibit the level of rigor one would expect in biomedical research, especially when studying multifactorial diseases such as cancer or atherosclerosis. The reporting of population differences in clinical research is characterized by large disparities in practices, and fraught with methodological issues and inconsistencies. The actual designations such as "Black" or "Asian" refer to broad and heterogeneous groups, with a great discrepancy among countries. Moreover, the use of obsolete concepts such as "Caucasian" is unfortunate and imprecise. The use of adequate labeling to reflect the scientific hypothesis needs to be promoted. Furthermore, the use of "race/ethnicity" as a unique cause of human heterogeneity may distract from investigating other factors related to a medical condition, particularly if this label is employed as a proxy for cultural habits, diet, or environmental exposure. In addition, the wide range of opinions among researchers does not facilitate the attempts made for resolving this heterogeneity in labeling. "Race", "ethnicity", "ancestry", "geographical origin", and other similar concepts are saturated with meanings. Even if the feasibility of a global consensus on labeling seems difficult, geneticists, sociologists, anthropologists, and ethicists should help develop policies and practices for the biomedical field. This article is protected by copyright. All rights reserved.

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.

We read with great interest the perspective by Bumpus (1), who describes the issue of overrepresenting individuals of European ancestry in pharmacological trials. The author highlights the inequities this can translate into and the efforts needed in reporting ethnicity in trials, in line with the STROPS guideline (2). However, this raises several concerns.

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.

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.