Abstract
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.
Highlights
Since the early 1960s, protein sequence comparisons have become increasingly important in molecular evolutionary research (Doolittle & Blombaeck, 1964; Fitch & Margoliash, 1967; Margoliash, 1963; Zuckerkandl & Pauling, 1962)
Using datasets from the 1000 Genomes (1KG) Project Phase 3 dataset (Auton et al, 2015), we found that missense single nucleotide polymorphisms (SNPs) from the slowest evolving set of proteins, especially those with high minor allele frequency (MAF), were enriched with conservative amino acid changes, consistent with these changes being under weaker natural selection
We divided the proteins into several groups of different evolutionary rates, and compared the proportion of conservative amino acid substitutions in each group
Summary
Since the early 1960s, protein sequence comparisons have become increasingly important in molecular evolutionary research (Doolittle & Blombaeck, 1964; Fitch & Margoliash, 1967; Margoliash, 1963; Zuckerkandl & Pauling, 1962). An apparent relationship between protein sequence divergence and time of separation led to the molecular clock hypothesis, which assumes a constant and similar evolutionary rate among species (Kumar, 2005; Margoliash, 1963; Zuckerkandl & Pauling, 1962). The molecular clock, in turn, led Kimura to propose the neutral theory to explain nature: sequence differences between species were thought to be largely due to neutral changes rather than adaptive evolution (Kimura, 1968). The neutral theory remains an incomplete explanatory theory (Hu et al, 2013; Kern & Hahn, 2018)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
