Using disease-associated coding sequence variation to investigate functional compensation by human paralogous proteins

摘要: Gene duplication enables the functional diversification in species. It is thought that duplicated genes may be able to compensate if function of one gene copies disrupted. This possibility extensively debated with some studies reporting proteome-wide compensation, whereas others suggest compensation among only recent duplicates or no at all. We report results from a systematic molecular evolutionary analysis test predictions hypothesis. contrasted density Mendelian disease-associated single nucleotide variants (dSNVs) proteins discernable paralogs (singletons) dSNV found multigene families. Under hypothesis, we expected find greater numbers dSNVs singletons due lack any compensating partners. Our analyses produced an opposite pattern; have over 35% higher than singletons. these patterns are concordant similar differences rates amino acid evolution (ie, constraints), as evolved 33% slower constraint explanation robust family sizes, ages (young vs. old duplicates), and degrees sequence similarities paralogs. Therefore, human variation does not exhibit significant signals paralogous proteins, but rather hypothesis provides better for observed neutral polymorphisms genome.