Role of Duplicate Genes in Robustness against Deleterious Human Mutations

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.

A Comprehensive Dataset of Genes with a Loss-of-Function Mutant Phenotype in Arabidopsis

“…Similar patterns have been noted for RNA interference phenotypes in C. elegans (Conant and Wagner, 2004). In humans, genes without a potential homolog in the genome are several times more likely to be associated with a disease mutation than genes with a homolog (Hsiao and Vitkup, 2008). In mouse, duplicated and unique genes at first appeared to be equally represented among knockout collections of essential genes (Liao and Zhang, 2007).…”

“…The role of gene duplications in modulating the phenotypes of loss-of-function mutations has been examined in a variety of eukaryotes, including yeast (Gu et al, 2003;Ihmels et al, 2007), C. elegans (Conant and Wagner, 2004), mouse (Liao and Zhang, 2007;Makino et al, 2009), and humans (Hsiao and Vitkup, 2008). Two fundamental questions have frequently been raised.…”

Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics

“…Genes harboring nonsense SNPs were also found to belong to gene families of higher than average size [Ng et al, 2008], suggesting that some functional redundancy may exist between paralogous human genes. In support of this idea, Hsiao and Vitkup [2008] reported that those human genes that have a homologue with Z90% sequence similarity are approximately three times less likely to harbor disease-causing mutations than genes with less closely related homologues. They interpreted their findings in terms of ''genetic robustness'' against null mutations, with the duplicated sequences providing ''back-up'' by potentiating the functional compensation/complementation of homologous genes in the event that they acquire deleterious mutations.…”

Survival and innovation: The role of mutational robustness in evolution

“…While gene duplicates have been considered to have a major role in mutational robustness through genetic redundancy [79], the persistence of genes in duplicate clashes with the evolutionary instability of genetic redundancy. Nonetheless, evidence support a role of duplicated genes in mutational robustness: a) The deletion of singletons in yeast have larger fitness effects than the deletion of duplicates [80]; b) Deletion of gene copies in yeast are often functionally compensated by the other gene copy, thereby having lower effects on genetic interactions for duplicates than singletons [81]; c) Duplicates present higher robustness than singletons to transient gene knock-downs in Caenorhabditis elegans [82], and d) Duplicates contribute to back-up against deleterious mutations in humans [83]. Against this evidence, using synthetic lethality genetic maps it has been shown that duplicates only account for 25% of the genetic robustness of yeast [84].…”