Using Disease-Associated Coding Sequence Variation to Investigate Functional Compensation by XXXX Paralogous Proteins.

@entity1 @entity4334 @entity3689 @entity1538
UNASSIGNED: 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 @entity1538 , 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 @entity4334 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 @entity3689 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 @entity3689 sequence similarities among paralogs. Therefore, disease-associated @entity1 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 @entity1 genome.
