Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G.
Human leukocyte antigen-G (HLA-G) has well-recognized immunosuppressive properties modulating the activity of many immune system cells, and polymorphisms observed at the HLA-G 5' upstream regulatory region (5'URR) may influence gene transcriptional regulation. In this study, we characterized the sequence variation and haplotype structure of the HLA-G 5'URR in worldwide populations to investigate the evolutionary history of the HLA-G promoter and shed some light into the mechanisms that may underlie HLA-G expression control. A 1.4-kb region, encompassing the known HLA-G regulatory elements, was sequenced in three African populations from Senegal, Benin and Congo, and data were combined with those available in the literature, resulting in a total of 1411 individuals from 21 worldwide populations. High levels of nucleotide and haplotype diversities, excess of intermediate-frequency variants and reduced population differentiation were observed at this locus when compared with the background genomic variation. These features support a strong molecular signature of balancing selection at HLA-G 5'URR, probably as a result of the competing needs to maintain both a maternal-fetal immune tolerance and an efficient host immune response to invading pathogens during human evolution. An extended analysis of a 300-kb region surrounding HLA-G revealed that this region is not involved in a hitchhiking effect and may be the direct target of selection.
1] Institute of Research for Development, Mixed Research Unit 216 MERIT, Paris, France [2] Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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Gineau
Institute of Evolutionary Biology, CEXS-UPF-PRBB, Catalonia, Barcelona, Spain.
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Luisi
Faculdade de Medicina, UNESP-Univ Estatual Paulista, Departamento de Patologia, Botucatu, Brazil.
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Castelli
IRD, UMR 216, Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance (CERPAGE); Faculté des Sciences de la Santé, Cotonou, Bénin.
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Milet
IRD, UMR 216, Centre d'Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l'Enfance (CERPAGE); Faculté des Sciences de la Santé, Cotonou, Bénin.
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Courtin
Division of Clinical Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
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Cagnin
1] Institute of Research for Development, Mixed Research Unit 216 MERIT, Paris, France [2] Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France [3] Université Paris Sud, Kremlin-Bicêtre, France.
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Patillon
Institute of Evolutionary Biology, CEXS-UPF-PRBB, Catalonia, Barcelona, Spain.
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Laayouni
1] Commissariat à l'Energie Atomique et aux Energies Alternatives, institut des Maladies Emergentes et des Thérapies Innovantes, Service de Recherches en Hémato-Immunologie, Hôpital Saint-Louis, Paris, France [2] Université Paris Diderot, Sorbonne Paris Cité, UMR_E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
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Moreau
Division of Clinical Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.
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Donadi
1] Institute of Research for Development, Mixed Research Unit 216 MERIT, Paris, France [2] Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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Garcia
1] Institute of Research for Development, Mixed Research Unit 216 MERIT, Paris, France [2] Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
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Sabbagh
D005828:Genetics, Population; D059951:HLA-G Antigens / Q000235:genetics* / Q000276:immunology*; D006239:Haplotypes; D006801:Humans; D007108:Immune Tolerance; D015810:Linkage Disequilibrium; D011110:Polymorphism, Genetic; D050436:Regulatory Elements, Transcriptional; D012641:Selection, Genetic
D059951:HLA-G Antigens