title: Using Disease-Associated Coding Sequence Variation to Investigate Functional Compensation by Human Paralogous Proteins.
abstract: Gene duplication enables the functional diversification in species. It is thought that duplicated genes may be able to compensate if the function of one of the gene copies is disrupted. This possibility is extensively debated with some studies reporting proteome-wide compensation, whereas others suggest functional compensation among only recent gene duplicates or no compensation at all. We report results from a systematic molecular evolutionary analysis to test the predictions of the functional compensation hypothesis. We contrasted the density of Mendelian disease-associated single nucleotide variants (dSNVs) in proteins with no discernable paralogs (singletons) with the dSNV density in proteins found in multigene families. Under the functional compensation hypothesis, we expected to find greater numbers of dSNVs in singletons due to the lack of any compensating partners. Our analyses produced an opposite pattern; paralogs have over 35% higher dSNV density than singletons. We found that these patterns are concordant with similar differences in the rates of amino acid evolution (ie, functional constraints), as the proteins with paralogs have evolved 33% slower than singletons. Our evolutionary constraint explanation is robust to differences in family sizes, ages (young vs. old duplicates), and degrees of amino acid sequence similarities among paralogs. Therefore, disease-associated human variation does not exhibit significant signals of functional compensation among paralogous proteins, but rather an evolutionary constraint hypothesis provides a better explanation for the observed patterns of disease-associated and neutral polymorphisms in the human genome.
authors.affiliation: Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA, USA.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Miura
authors.affiliation: School of Life Sciences, Arizona State University, Tempe, AZ, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tate
authors.affiliation: Institute for Genomics and Evolutionary Medicine, Temple University, Philadelphia, PA, USA. ; Department of Biology, Temple University, Philadelphia, PA, USA. ; Center for Excellence in Genome Medicine and Research, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
keywords: Mendelian disease; evolutionary rate; functional compensation; gene duplication; single nucleotide variants