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dc.creatorMiura, S
dc.creatorTate, S
dc.creatorKumar, S
dc.identifier.otherCY3SG (isidoc)
dc.identifier.other26604664 (pubmed)
dc.description.abstract© the authors, publisher and licensee Libertas Academica Limited. 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 evo-lutionary 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 analy-ses 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.
dc.relation.haspartEvolutionary Bioinformatics
dc.relation.isreferencedbySAGE Publications
dc.subjectfunctional compensation
dc.subjectgene duplication
dc.subjectMendelian disease
dc.subjectsingle nucleotide variants
dc.subjectevolutionary rate
dc.titleUsing disease-associated coding sequence variation to investigate functional compensation by human paralogous proteins
dc.type.genreJournal Article
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact
dc.creator.orcidKumar, Sudhir|0000-0002-9918-8212

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