A Comprehensive Study of Polymorphic Sites along the HLA-G Gene: Implication for Gene Regulation and Evolution

• Published in: Molecular biology and evolution 2011-11, Vol.28 (11), p.3069-3086
• Main Authors: Castelli, Erick C., Mendes-Junior, Celso T., Veiga-Castelli, Luciana C., Roger, Michel, Moreau, Philippe, Donadi, Eduardo A.
• Format: Article
• Language: English
• Subjects: 3' Untranslated regions; Base Sequence; Binding sites; Bone marrow; Brazil; DNA Primers - genetics; Donors; Evolution; Evolution, Molecular; Evolutionary genetics; Gene expression; Gene Expression Regulation - genetics; Gene polymorphism; Gene regulation; Genetic Variation; Haplotypes; Haplotypes - genetics; Histocompatibility antigen HLA; HLA-G Antigens - genetics; Humans; Immune response; Immunomodulation; Linkage Disequilibrium; Lymphocytes T; Molecular Sequence Data; Natural killer cells; Nucleotides; Polymorphism; Polymorphism, Genetic; Population studies; Proteins; Regulatory sequences; Selection, Genetic; Sequence Analysis, DNA
• ISSN: 0737-4038; 1537-1719
• DOI: 10.1093/molbev/msr138

HLA-G molecule plays an important role on immune response regulation and has been implicated on the inhibition of T and natural killer cell cytolytic function and inhibition of allogeneic T-cell proliferation. Due to its immune-modulator properties, the HLA-G gene expression has been associated with the outcome of allograft and of autoimmune, infectious, and malignant disorders. Several lines of evidence indicate that HLA-G polymorphisms at the 5′-upstream regulatory region (5′ URR) and 3′-untranslated region (3′ UTR) may influence the HLA-G expression levels. Because Brazilians represent one of the most heterogeneous populations in the world with the widest HLA-G coding region variability already detected among the studied populations, a high level of variability and haplotype diversity would be expected in Brazilians. On this basis, the 5′ URR, coding, and 3′ UTR variability were evaluated in a Brazilian series consisting of 100 healthy bone marrow donors, as well as the linkage disequilibrium pattern along the gene and the extended haplotypes encompassing several gene segment variations. The HLA-G locus seems to present six different HLA-G lineages showing functional variations mainly in nucleotides of the regulatory regions. Differences were observed at the 5′ URR in positions that either coincide with or are close to transcription factor-binding sites and at the 3′ UTR mainly in positions that have already been reported to influence HLA-G mRNA availability. We report several lines of evidence for balancing selection acting on the regulatory regions, which may indicate that these HLA-G lineages may be related to the differential HLA-G expression profiles.