Evidence of balancing selection at the HLA-G promoter region

Abstract

HLA-G is a class Ib HLA gene with unique tissue expression pattern and immunomodulatory properties. Polymorphisms in the HLA-G promoter region have been associated with miscarriage and asthma, whereas expression levels have been associated with a wide range of pathologic conditions as well as survival of embryos after in vitro fertilization and of organs after transplantation. Here, we characterize the sequence variation and haplotype structure of the HLA-G promoter and flanking sequences in 44 African Americans, 47 European Americans and 43 Han Chinese by haplotype-specific PCR and sequencing. In all three populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, and a genealogy with two common haplotypes separated by deep branches, features that are suggestive of balancing selection acting in this region. Comparisons to HLA-A and a pseudogene, HLA-J, suggested that the observed pattern of sequence variation in the HLA-G promoter region is not likely due to other selected HLA genes. We suggest that the mechanism for this selection is related to the highly regulated expression pattern of HLA-G and that high- and low-expressing promoters may be favored under temporally and/or spatially varying selective pressures.

Distinctive Immunological Functions of HLA-G

“…The region up-stream from the transcriptional start site of HLA-G contains 27 different polymorphisms but only 13 of them are within or very close to known transcription factor binding sites or regulatory elements (Hviid et al, 1999;Ober et al, 2003;Tan et al, 2005). Interestingly, all the 27 polymorphisms are in strong linkage disequilibrium (LD) and define 13 unique promoter haplotypes (Ober et al, 2003;Tan et al, 2005). Among the 5' URR polymorphisms, only the -725C/G/T single nucleotide polymorphism (SNP) has been associated with HLA-G expression.…”

“…Several SNPs at 3'UTR of HLA-G locus have been identified (Castelli et al, 2009). Among them, the +3142 C/G SNP has been proposed to be critically involved in HLA-G regulation since it is associated with asthma (Tan et al, 2005). The G variant of a G/C SNP at position +3142 of the 3'UTR has been hypothesized to increase the affinity of the resulting mRNA for miR-148a, miR-148b and miR-152 (Veit and Chies, 2009).…”

Seleção balanceadora no genoma humano: relevância biológica e consequências deletérias

“…Outro exemplo é o HLA-G, também entre os nossos candidatos e com uma ampla literatura descrevendo padrões complexos de expressão (p.ex. Tan et al, 2005). Assim, testamos se tais padrões são recorrentes entre nossos genes e detectamos um excesso significativo de genes com expressão em apenas um tecido humano: 12 com expressão na glândula adrenal e 25 com expressão no pulmão.…”

Genética de populações em genes de função imunológica: um estudo em populações Ameríndias

“…Há fortes evidências de que a seleção natural também atua sobre regiões cis-reguladoras (WRAY, 2007). Evidências de seleção balanceadora têm sido identificadas em regiões cis-reguladoras de genes de função imunológica, tais como HLA-G (TAN et al, 2005) e HLA-DPA1 e HLA-DPB1 (LIU et al, 2006).…”

“…Estudos prévios analisaram os efeitos de seleção sobre populações Africanas, Européias e Asiáticas (TAN et al, 2005;YAWATA et al, 2006;NORMAN et al, 2007). O presente trabalho propõe o estudo dos efeitos da seleção natural sobre populações Ameríndias a fim de investigar se a seleção natural, que parece ser relevante numa escala global deixa uma marca quando populações de escalas geográficas menores e história evolutiva recente, como o caso das populações Ameríndias, são analisadas.…”