role of duplicate genes in robustness against deleterious human mutations复制基因的作用在鲁棒性对有害人类突变.pdfVIP

Role of Duplicate Genes in Robustness against Deleterious Human Mutations Tzu-Lin Hsiao1,2, Dennis Vitkup1,2* 1 Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, United States of America, 2 Department of Biomedical Informatics, Columbia University, New York, New York, United States of America Abstract It is now widely recognized that robustness is an inherent property of biological systems [1,2,3]. The contribution of close sequence homologs to genetic robustness against null mutations has been previously demonstrated in simple organisms [4,5]. In this paper we investigate in detail the contribution of gene duplicates to back-up against deleterious human mutations. Our analysis demonstrates that the functional compensation by close homologs may play an important role in human genetic disease. Genes with a 90% sequence identity homolog are about 3 times less likely to harbor known disease mutations compared to genes with remote homologs. Moreover, close duplicates affect the phenotypic consequences of deleterious mutations by making a decrease in life expectancy significantly less likely. We also demonstrate that similarity of expression profiles across tissues significantly increases the likelihood of functional compensation by homologs. Citation: Hsiao T-L, Vitkup D (2008) Role of Duplicate Genes in Robustness against Deleterious Human Mutations. PLoS Genet 4(3): e1000014. doi:10.1371/ journal.pgen.1000014 Editor: Wayne N. Frankel, The Jackson Laboratory, United States of America Received June 14, 2007; Accepted January 30, 2008; Published March 14, 2008 Copyright: 2008 Hsiao and Vitkup. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and so