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

• Published in: Genes and immunity 2015-01, Vol.16 (1), p.57-70
• Main Authors: Gineau, L, Luisi, P, Castelli, E C, Milet, J, Courtin, D, Cagnin, N, Patillon, B, Laayouni, H, Moreau, P, Donadi, E A, Garcia, A, Sabbagh, A
• Format: Article
• Language: English
• Subjects: 45/23; 45/77; 631/208/457/649; Biomedical and Life Sciences; Biomedicine; Cancer Research; Fetuses; Gene Expression; Gene regulation; Genetic aspects; Genetic polymorphisms; Genetic research; Genetic transcription; Genetics, Population; Genomics; Haplotypes; Histocompatibility antigen HLA; Histocompatibility antigens; HLA histocompatibility antigens; HLA-G Antigens - genetics; HLA-G Antigens - immunology; Human Genetics; Humans; Immune response; Immune system; Immune Tolerance; Immunological tolerance; Immunology; Immunosuppressive agents; Linkage Disequilibrium; Natural selection; original-article; Physiological aspects; Polymorphism, Genetic; Population differentiation; Regulatory Elements, Transcriptional; Regulatory sequences; Selection, Genetic; Transcription
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2014.63

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.