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Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G

Genes & Immunity volume 16, pages 57–70 (2015)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the binational collaborative research program CAPES-COFECUB (grant #653/09) and by the Spanish National Institute for Bioinformatics (www.inab.org). LG was supported by grants from Région Ile-de-France. PL was supported by a PhD fellowship from ‘Acción Estratrégica de Salud, en el Marco del Plan Nacional de Investigacio'n Científica, Desarrollo e Innovación Tecnológica 2008–2011’ from Instituto de Salud Carlos III. BP was supported by a PhD fellowship from the doctoral program in Public Health from Paris Sud University. ECC was supported by the Brazilian Council for Scientific and Technological Development—CNPq (grant # 304471/2013-5). EAD was supported by the Brazilian Council for Scientific and Technological Development—CNPq Project (grant # 476036/2013-5).

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Authors and Affiliations

  1. Institute of Research for Development, Mixed Research Unit 216 MERIT, Paris, France

    L Gineau, B Patillon, A Garcia & A Sabbagh

  2. Faculté de Pharmacie, Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    L Gineau, B Patillon, A Garcia & A Sabbagh

  3. Institute of Evolutionary Biology, CEXS-UPF-PRBB, Catalonia, Barcelona, Spain

    P Luisi & H Laayouni

  4. Departamento de Patologia, Faculdade de Medicina, UNESP—Univ Estatual Paulista, Botucatu, Brazil

    E C Castelli

  5. IRD, UMR 216, Centre d’Etude et de Recherche sur le Paludisme Associé à la Grossesse et à l’Enfance (CERPAGE),

    J Milet & D Courtin

  6. Faculté des Sciences de la Santé, Cotonou, Bénin

    J Milet & D Courtin

  7. Division of Clinical Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil

    N Cagnin & E A Donadi

  8. Université Paris Sud, Kremlin-Bicêtre, France

    B Patillon

  9. 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

    P Moreau

  10. Université Paris Diderot, Sorbonne Paris Cité, UMR_E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France

    P Moreau

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  1. L Gineau
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Gineau, L., Luisi, P., Castelli, E. et al. Balancing immunity and tolerance: genetic footprint of natural selection in the transcriptional regulatory region of HLA-G. Genes Immun 16, 57–70 (2015). https://doi.org/10.1038/gene.2014.63

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