ABCB2 p.Val518Leu
| Predicted by SNAP2: | A: D (91%), C: D (63%), D: D (95%), E: D (85%), F: N (57%), G: D (80%), H: D (80%), I: N (78%), K: D (95%), L: N (87%), M: N (72%), N: D (85%), P: D (91%), Q: D (80%), R: D (85%), S: D (75%), T: D (95%), W: D (75%), Y: D (80%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D, |
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[hide] An evolutionary analysis of antigen processing and... PLoS Genet. 2014 Mar 27;10(3):e1004189. doi: 10.1371/journal.pgen.1004189. eCollection 2014 Mar. Forni D, Cagliani R, Tresoldi C, Pozzoli U, De Gioia L, Filippi G, Riva S, Menozzi G, Colleoni M, Biasin M, Lo Caputo S, Mazzotta F, Comi GP, Bresolin N, Clerici M, Sironi M
An evolutionary analysis of antigen processing and presentation across different timescales reveals pervasive selection.
PLoS Genet. 2014 Mar 27;10(3):e1004189. doi: 10.1371/journal.pgen.1004189. eCollection 2014 Mar., [PMID:24675550]
Abstract [show]
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.
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No. Sentence Comment
293 Two distantly related haplotypes are observed in YRI (YRI-hapI and YRI-hapII, Figure 7C) and both carry at least one distinctive nonsynonymous variant (V518L and G77R plus Q788K, respectively).
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ABCB2 p.Val518Leu 24675550:293:152
status: NEW398 Interestingly, one of the putative balancing selection targets in TAP1, the V518L variant, is located in the peptide binding domain, close to a positively selected site (516Q), and defines a minor haplotype in YRI; this variant might affect the affinity of TAP1 for one or more antigenic peptides.
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ABCB2 p.Val518Leu 24675550:398:76
status: NEW