Like Wings of a Bird: Functional Divergence and Complementarity between HLA-A and HLA-B Molecules

Article Article scientifique Article Like Wings of a Bird: Functional Divergence and Complementarity between HLA-A and HLA-B Molecules eng 2020-12-15 2021 author Di Da Laboratory of Anthropology, Genetics and Peopling History (AGP Lab), Department of Genetics and Evolution–Anthropology Unit, University of Geneva, Geneva, Switzerland 663072 author Nunes Jose Manuel Laboratory of Anthropology, Genetics and Peopling History (AGP Lab), Department of Genetics and Evolution–Anthropology Unit, University of Geneva, Geneva, Switzerland 122321 Département de génétique et évolution (Genev) (BIANI) author Jiang Wei Department of Plant Sciences, University of Cambridge, Cambridge, United Kingdom 85050 author Sanchez-Mazas Alicia Laboratory of Anthropology, Genetics and Peopling History (AGP Lab), Department of Genetics and Evolution–Anthropology Unit, University of Geneva, Geneva, Switzerland 22545 Département de génétique et évolution (Genev) (BIANI) 1580-1594 10.1093/molbev/msaa325 33320202 0737-4038 PMC8355449 https://academic.oup.com/mbe/article/38/4/1580/6035138 <p>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 human 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 are still unknown. To address this issue, we carried out extensive data analyses (among which factorial correspondence analysis and linear modeling) 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 defense. 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 intraprotein 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.</p> HLA allele frequencies HLA diversity HLA duplicated genes Balancing selection Functional complementarity Peptide-binding predictions Dewey 590 Swiss National Science Foundation Early human settlements in contrasting environments: HLA molecular variation and its link to population expansions and immune adaptation 144180 CH Projects 44 Département de génétique et évolution 162 false Molecular biology and evolution 38 4 32e0cdd6-72f1-4192-a024-e92fafb030d2 Article (Published version) Public Article-scientifique-from-crossref.pdf 896027 application/pdf CC BY-NC-4.0 7b96d01851741042f89005d27782a4218e2ef62b5a41dd626350c3b3863c932d openAccess Faculté des sciences / Section de biologie / Département de génétique et évolution

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Like Wings of a Bird: Functional Divergence and Complementarity between HLA-A and HLA-B Molecules	Molecular biology and evolution			2021	62	59

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