Forni Diego, Cagliani Rachele, Tresoldi Claudia, Pozzoli Uberto, De Gioia Luca, Filippi Giulia, Riva Stefania, Menozzi Giorgia, Colleoni Marta, Biasin Mara, Lo Caputo Sergio, Mazzotta Francesco, Comi Giacomo P, Bresolin Nereo, Clerici Mario, Sironi Manuela
Scientific Institute IRCCS E. MEDEA, Bioinformatics, Bosisio Parini, Italy.
Department of Biotechnology and Biosciences, University of Milan-Bicocca, Milan, Italy.
PLoS Genet. 2014 Mar 27;10(3):e1004189. doi: 10.1371/journal.pgen.1004189. eCollection 2014 Mar.
The antigenic repertoire presented by MHC molecules is generated by the antigen processing and presentation (APP) pathway. We analyzed the evolutionary history of 45 genes involved in APP at the inter- and intra-species level. Results showed that 11 genes evolved adaptively in mammals. Several positively selected sites involve positions of fundamental importance to the protein function (e.g. the TAP1 peptide-binding domains, the sugar binding interface of langerin, and the CD1D trafficking signal region). In CYBB, all selected sites cluster in two loops protruding into the endosomal lumen; analysis of missense mutations responsible for chronic granulomatous disease (CGD) showed the action of different selective forces on the very same gene region, as most CGD substitutions involve aminoacid positions that are conserved in all mammals. As for ERAP2, different computational methods indicated that positive selection has driven the recurrent appearance of protein-destabilizing variants during mammalian evolution. Application of a population-genetics phylogenetics approach showed that purifying selection represented a major force acting on some APP components (e.g. immunoproteasome subunits and chaperones) and allowed identification of positive selection events in the human lineage. We also investigated the evolutionary history of APP genes in human populations by developing a new approach that uses several different tests to identify the selection target, and that integrates low-coverage whole-genome sequencing data with Sanger sequencing. This analysis revealed that 9 APP genes underwent local adaptation in human populations. Most positive selection targets are located within noncoding regions with regulatory function in myeloid cells or act as expression quantitative trait loci. Conversely, balancing selection targeted nonsynonymous variants in TAP1 and CD207 (langerin). Finally, we suggest that selected variants in PSMB10 and CD207 contribute to human phenotypes. Thus, we used evolutionary information to generate experimentally-testable hypotheses and to provide a list of sites to prioritize in follow-up analyses.
主要组织相容性复合体（MHC）分子所呈现的抗原库是由抗原加工与呈递（APP）途径产生的。我们在种间和种内水平分析了45个参与APP的基因的进化历史。结果表明，11个基因在哺乳动物中发生了适应性进化。几个正选择位点涉及对蛋白质功能至关重要的位置（例如，TAP1肽结合结构域、朗格汉斯蛋白的糖结合界面以及CD1D转运信号区域）。在CYBB中，所有选择位点都聚集在两个伸入内体腔的环中；对导致慢性肉芽肿病（CGD）的错义突变的分析表明，在同一基因区域存在不同的选择力作用，因为大多数CGD替代涉及在所有哺乳动物中保守的氨基酸位置。至于ERAP2，不同的计算方法表明，正选择在哺乳动物进化过程中推动了蛋白质不稳定变体的反复出现。群体遗传学系统发育方法的应用表明，纯化选择是作用于一些APP成分（例如免疫蛋白酶体亚基和伴侣蛋白）的主要力量，并允许识别人类谱系中的正选择事件。我们还通过开发一种新方法来研究人类群体中APP基因的进化历史，该方法使用几种不同的测试来识别选择靶点，并将低覆盖度全基因组测序数据与桑格测序相结合。该分析表明，9个APP基因在人类群体中经历了局部适应。大多数正选择靶点位于髓系细胞中具有调控功能的非编码区域，或作为表达数量性状位点起作用。相反，平衡选择针对TAP1和CD207（朗格汉斯蛋白）中的非同义变体。最后，我们认为PSMB10和CD207中的选择变体有助于人类表型。因此，我们利用进化信息来生成可实验验证的假设，并提供一份在后续分析中优先考虑的位点列表。
