Enrichment in conservative amino acid changes among fixed and standing missense variations in slow evolving proteins

Proteins were first used in the early 1960s to discover the molecular clock dating method and remain in common usage today in phylogenetic inferences based on neutral variations. To avoid substitution saturation, it is necessary to use slow evolving genes. However, it remains unclear whether fixed and standing missense changes in such genes may qualify as neutral. Here, based on the evolutionary rates as inferred from identity scores between orthologs in human and Macaca monkey, we found that the fraction of conservative amino acid mismatches between species was significantly higher in slow evolving proteins. We also examined the single nucleotide polymorphisms (SNPs) by using the 1000 genomes project data and found that missense SNPs in slow evolving proteins also had higher fraction of conservative changes, especially for common SNPs, consistent with more natural selection for SNPs, particularly rare ones, in fast evolving proteins. These results suggest that fixed and standing missense variations in slow evolving proteins are more likely to be neutral and hence better qualified for use in phylogenetic inferences.