Seleção natural em genes HLA e seu efeito sobre regiões adjacentes do genoma

Abstract

The MHC is a genomic region that contains genes with a central role in the adaptive immune response. Genes in the MHC region, in particular the HLA genes of humans, are involved in the differential susceptibility and resistance to infectious diseases, predisposition to autoimmune diseases and the rejection of transplanted organs. These findings have fueled a series of studies on patterns of genetic variation at HLA genes, which have conclusively demonstrated that their variation deviates from neutral expectations. Such strong evidence of natural selection, with few counterparts in the remainder of the human genome, raise a series of questions concerning the specific evolutionary forces acting on this region and their genomic implications for the evolution of the region as a whole. This work investigates how natural selection affects and is affected by the diversity of genes that are physically linked to those that are units of selection. Our expectation is that strong selection on HLA genes may interfere with the efficacy of selection in removing deleterious variants at closely linked loci. Specifically, by using functional annotations of genetic variants, we test whether sets of genes physically linked to the strongly selected HLA loci show a higher diversity than would be expected in the absence of balancing selection and genetic hitchhiking caused by it, and if this diversity is enriched for putatively deleterious variants. By analysing the ratio of nonsynonymous to synonymous polymorphisms (and several related statistics) we were able to show that loci close to HLA genes are harboring an excess of nonsynonymous (and hence potentially deleterious) variation. The deleteriousness was confirmed by employing Polyphen 2-a software that uses nucleotide sequence conservation and protein structure information to classify variants as deleterious or not-and computing statistics such as P del /P n and P del /P s. According to McDonald-Kreitman tests and the Neutrality Index, however, part of this putatively deleterious variation reaches fixation over long timespans, suggesting that selection at the HLA genes may be interfering with both the transient patterns of polymorphism and substitution processes.

Diferenciação populacional em genes sob forte seleção balanceadora:um estudo de caso com genes HLA.

“…Peri-HLA genes were defined as those that flank the HLA genes and have higher diversity relative to the average of chromosome 6 in the Yoruba (YRI) population (Mendes, 2013), indicating that their increased polymorphism is driven by hitchhiking due to the strongly selected HLA loci. The 25 peri-HLA genes are shown in Supporting Information (Appendix S2.2).…”