Furlong Rebecca F, Yang Ziheng
Department of Biology, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK.
J Mol Evol. 2008 Apr;66(4):384-94. doi: 10.1007/s00239-008-9092-6. Epub 2008 Mar 18.
The class II genes of the major histocompatibility complex encode proteins which play a crucial role in antigen presentation. They are among the most polymorphic proteins known, and this polymorphism is thought to be the result of natural selection. To understand the selective pressure acting on the protein and to examine possible differences in the evolutionary dynamics among species, we apply maximum likelihood models of codon substitution to analyze the DRB genes of six mammalian species: human, chimpanzee, macaque, tamarin, dog, and cow. The models account for variable selective pressures across codons in the gene and have the power to detect amino acid residues under either positive or negative selection. Our analysis detected positive selection in the DRB genes in each of the six mammals examined. Comparison with structural data reveals that almost all amino acid residues inferred to be under positive selection in humans are in the peptide binding region (PBR) and are in contact with the antigen side chains, although residues outside of but close to the PBR are also detected. Strong purifying selection is also detected in the PBR, at sites which contact the antigen and at sites which may be involved in dimerization or T cell binding. The analysis demonstrates the utility of the random-sites analysis even when structural information is available. The different mammalian species are found to share many positively or negatively selected sites, suggesting that their functional roles have remained very similar in the different species, despite the different habitats and pathogens of the species.
主要组织相容性复合体的II类基因编码在抗原呈递中起关键作用的蛋白质。它们是已知的多态性最高的蛋白质之一，这种多态性被认为是自然选择的结果。为了了解作用于该蛋白质的选择压力，并研究物种间进化动态的可能差异，我们应用密码子替换的最大似然模型来分析六种哺乳动物的DRB基因：人类、黑猩猩、猕猴、绢毛猴、狗和牛。这些模型考虑了基因中不同密码子的可变选择压力，并有能力检测处于正选择或负选择下的氨基酸残基。我们的分析在所有六种被检测的哺乳动物的DRB基因中都检测到了正选择。与结构数据的比较表明，几乎所有推断在人类中处于正选择下的氨基酸残基都在肽结合区域（PBR），并且与抗原侧链接触，不过在PBR之外但靠近PBR的残基也被检测到。在PBR中，在与抗原接触的位点以及可能参与二聚化或T细胞结合的位点也检测到了强烈的纯化选择。该分析表明，即使有结构信息，随机位点分析也是有用的。发现不同的哺乳动物物种共享许多正选择或负选择的位点，这表明尽管这些物种的栖息地和病原体不同，但它们在不同物种中的功能作用仍然非常相似。
