title: Conserved proteins are fragile.
abstract: Levels of selective constraint vary among proteins. Although strong constraint on a protein is often attributed to its functional importance, evolutionary rate may also be limited if a protein is fragile, such that a large proportion of amino acid replacements reduce its fitness. To determine the relative contributions of essentiality and fragility to selective constraint, we compared relationships of selection against nonsense mutations (snon) and selection against missense mutations (smis) to protein sequence conservation (Ka). As expected, snon is greater than smis; however, the correlation between smis and Ka is nearly three times stronger than the correlation between snon and Ka. Moreover, examination of relationships to gene expression level, tissue specificity, and number of protein-protein interactions shows that smis is more strongly correlated than snon to all three measures of biological function. Thus, our analysis reveals that slowly evolving proteins are under strong selective constraint primarily because they are fragile, and that this association likely exists because allowing a protein to function improperly, rather than removing it from a biological network, can negatively affect the functions of other molecules it interacts with and their downstream products.
authors.affiliation: Department of Biology, Pennsylvania State University.
authors.forename: Raquel
authors.initials: R
authors.lastname: Assis
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Kondrashov
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000235:genetics*; D000818:Animals; D005075:Biological Evolution; D018389:Codon, Nonsense; D017124:Conserved Sequence / Q000235:genetics*; D004330:Drosophila / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation; D008297:Male; D008957:Models, Genetic; D020125:Mutation, Missense; D009928:Organ Specificity; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D000596:Amino Acids; D018389:Codon, Nonsense; D011506:Proteins
keywords: evolutionary rate; natural selection; protein essentiality; protein evolution; selective constraint