title: Nonsynonymous substitution rate (Ka) is a relatively consistent parameter for defining fast-evolving and slow-evolving protein-coding genes.
abstract: BACKGROUND
  Mammalian genome sequence data are being acquired in large quantities and at enormous speeds. We now have a tremendous opportunity to better understand which genes are the most variable or conserved, and what their particular functions and evolutionary dynamics are, through comparative genomics.
  
  
  RESULTS
  We chose human and eleven other high-coverage mammalian genome data-as well as an avian genome as an outgroup-to analyze orthologous protein-coding genes using nonsynonymous (Ka) and synonymous (Ks) substitution rates. After evaluating eight commonly-used methods of Ka and Ks calculation, we observed that these methods yielded a nearly uniform result when estimating Ka, but not Ks (or Ka/Ks). When sorting genes based on Ka, we noticed that fast-evolving and slow-evolving genes often belonged to different functional classes, with respect to species-specificity and lineage-specificity. In particular, we identified two functional classes of genes in the acquired immune system. Fast-evolving genes coded for signal-transducing proteins, such as receptors, ligands, cytokines, and CDs (cluster of differentiation, mostly surface proteins), whereas the slow-evolving genes were for function-modulating proteins, such as kinases and adaptor proteins. In addition, among slow-evolving genes that had functions related to the central nervous system, neurodegenerative disease-related pathways were enriched significantly in most mammalian species. We also confirmed that gene expression was negatively correlated with evolution rate, i.e. slow-evolving genes were expressed at higher levels than fast-evolving genes. Our results indicated that the functional specializations of the three major mammalian clades were: sensory perception and oncogenesis in primates, reproduction and hormone regulation in large mammals, and immunity and angiotensin in rodents.
  
  
  CONCLUSIONS
  Our study suggests that Ka calculation, which is less biased compared to Ks and Ka/Ks, can be used as a parameter to sort genes by evolution rate and can also provide a way to categorize common protein functions and define their interaction networks, either pair-wise or in defined lineages or subgroups. Evaluating gene evolution based on Ka and Ks calculations can be done with large datasets, such as mammalian genomes.
  
  
  METHODS
  This article has been reviewed by Drs. Anamaria Necsulea (nominated by Nicolas Galtier), Subhajyoti De (nominated by Sarah Teichmann) and Claus O. Wilke.
authors.affiliation: CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, PR China.
authors.forename: Dapeng
authors.initials: D
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Shi
authors.initials: S
authors.lastname: Huang
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D019295:Computational Biology / Q000379:methods*; D019143:Evolution, Molecular; D014644:Genetic Variation; D016678:Genome / Q000235:genetics; D006801:Humans; D008322:Mammals / Q000235:genetics; D008958:Models, Molecular; D016366:Open Reading Frames / Q000235:genetics*; D010802:Phylogeny; D016415:Sequence Alignment; D013045:Species Specificity