Work

Why Human Disease-Associated Residues Appear as the Wild-Type in Other Species: Genome-Scale Structural Evidence for the Compensation Hypothesis

Year: 2014

Type: article

Abstract: Many human-disease associated amino acid residues (DARs) appear as the wild-type in other species. This phenomenon is commonly explained by the presence of compensatory residues in these other species that alleviate the deleterious effects of the DARs. The general validity of this hypothesis, however, is unclear, because few compensatory residues have been identified. Here we test the compensation hypothesis by assembling and analyzing 1,077 DARs located in 177 proteins of known crystal structures. Because destabilizing protein structures is a primary reason why DARs are deleterious, we focus on protein stability in this analysis. We discover that, in species where a DAR represents the wild-type, the destabilizing effect of the DAR is generally lessened by the observed amino acid substitutions in the spatial proximity of the DAR. This and other findings provide genome-scale evidence for the compensation hypothesis and have important implications for understanding epistasis in protein evolution and for using animal models of human diseases.

Source: Molecular Biology and Evolution

DOI: 10.1093/molbev/msu130

Authors: Jinrui Xu, Jianzhi Zhang

Institution: University of Michigan

Language: English

Topic: Evolution and Genetic Dynamics

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: bronze

Funders: University of Michigan, National Institutes of Health, College of Pharmacy, University of Michigan, National Institute of General Medical Sciences

Award: Pleiotropy: patterns, mechanisms, and evolutionary consequences