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

The process of molecular evolution has many elements that are not yet fully understood. Evolutionary rates are known to vary among protein coding and noncoding DNAs, and most of the observed changes in amino acid or nucleotide sequences are assumed to be non-adaptive by the neutral theory of molecular evolution. However, it remains unclear whether fixed and standing missense changes in slowly evolving proteins are more or less neutral compared to those in fast evolving genes. Here, based on the evolutionary rates as inferred from identity scores between orthologs in human and Rhesus Macaques (Macaca mulatta), we found that the fraction of conservative substitutions between species was significantly higher in their slowly evolving proteins. Similar results were obtained by using four different methods of scoring conservative substitutions, including three that remove the impact of substitution probability, where conservative changes require fewer mutations. We also examined the single nucleotide polymorphisms (SNPs) by using the 1000 Genomes Project data and found that missense SNPs in slowly evolving proteins also had a higher fraction of conservative changes, especially for common SNPs, consistent with more non-conservative substitutions and hence stronger natural selection for SNPs, particularly rare ones, in fast evolving proteins. These results suggest that fixed and standing missense variants in slowly evolving proteins are more likely to be neutral.