Common sequence variants affect molecular function more than rare variants

摘要: Any two unrelated individuals differ by about 10,000 single amino acid variants (SAVs). Do these impact molecular function? Experimental answers cannot answer comprehensively, while state-of-the-art prediction methods can. We predicted the functional impacts of SAVs within human and for between other species. Several surprising results stood out. Firstly, four (CADD, PolyPhen-2, SIFT, SNAP2) agreed 10 percentage points on rare with effect. However, they differed substantially common SAVs: SNAP2 predicted, average, more effect than SAVs. Given large ExAC data sets sampling 60,706 individuals, differences were extremely significant (p-value < 2.2e-16). provided evidence that might be closer to reality methods, due to its different focus in development. Secondly, we significantly higher fractions healthy species; difference increased distantly related The same trends maintained subsets only housekeeping proteins when moving from exomes 1,000 60,000 individuals. frozen at speciation maintain protein function, many a species bring crucial changes, better or worse.