High level of functional polymorphism indicates a unique role of natural selection at human immune system loci

Abstract

Several studies have shown that immune system proteins have on average a higher rate of amino acid evolution between different species of mammals than do most other proteins. To test whether immune-system-expressed loci show a correspondingly elevated rate of within-species nonsynonymous (amino acid altering) polymorphism, we examined gene diversity (heterozygosity) at 4,911 single nucleotide polymorphism (SNP) sites at 481 protein-coding loci. At loci with nonimmune functions, gene diversity at nonsynonymous SNP sites was typically lower than that at silent SNP sites (those not altering the amino acid sequence) in the same gene, a pattern that is an evidence of purifying selection acting to eliminate slightly deleterious variants. However, this pattern was not seen at nonsynonymous SNPs causing conservative amino acid replacements in immune system proteins, indicating that the latter are subject to a reduced level of functional constraint. Similarly, immune system genes showed higher gene diversities in their 5' noncoding regions than did other proteins. These results identified certain immune system loci that are likely to be subject to balancing selection that acts to maintain polymorphism in either coding or regulatory regions.

Codon-based tests of positive selection, branch lengths, and the evolution of mammalian immune system genes

“…The factors causing the relaxation of purifying selection in immune system genes remain poorly understood (Hughes et al 2005b). Many immune system proteins are involved in cell-cell signaling, and one hypothesis might be that the relaxation of purifying selection is a characteristic of proteins involved in such signaling in general and not of immune system proteins in particular.…”

“…Unlike the majority of cases with b N >b S , which occurred on short branches, the enhanced rate of non-synonymous substitution was most apparent in the longer branches of the tree. Thus, the results support a reduction of the strength of purifying selection in immune system genes in comparison to other genes.The factors causing the relaxation of purifying selection in immune system genes remain poorly understood (Hughes et al 2005b). Many immune system proteins are involved in cell-cell signaling, and one hypothesis might be that the relaxation of purifying selection is a characteristic of proteins involved in such signaling in general and not of immune system proteins in particular.…”

Interleukin-8 Polymorphisms Are Not Associated with Gastric Cancer Risk in a Polish Population

“…However, there also seem to be significant differences in the Kyugen data of between the CEPH parents (European descent) and those from East Asia, with an A allele frequency of 42% and 34%, respectively. In addition, there are other cytokine genes with significant genetic variation between different ethnic groups (30). It is possible that population-specific genetic variation in different genes in the same or related pathways could also contribute to cancer risk.…”

Large-Scale Evaluation of Genetic Variants in Candidate Genes for Colorectal Cancer Risk in the Nurses' Health Study and the Health Professionals' Follow-up Study

“…Overall, the SNP selection approach for this study was to examine 10 kb upstream and 10 kb downstream in accordance with design score validations based on Illumina in-house measurements and the 60-bp limitation (a SNP cannot be closer than 60 bp to another SNP on this OPA). After excluding SNPs with high r 2 (defined as r 2 z 0.8), we did a preliminary screen of the remaining 3,072 SNPs in the SNP500Cancer database (2)(3)(4)(5)(6)(7)(8)11). From the 3,072 SNP panel, the final SNP selection of the 1,536 polymorphisms chosen for the OPA included SNPs with a MAF of >3% in the unrelated (that is, parents) HapMap CEPH Utah (CEU, with European Genotyping Methods.…”