title: Estimates of the effect of natural selection on protein-coding content.
abstract: Analysis of natural selection is key to understanding many core biological processes, including the emergence of competition, cooperation, and complexity, and has important applications in the targeted development of vaccines. Selection is hard to observe directly but can be inferred from molecular sequence variation. For protein-coding nucleotide sequences, the ratio of nonsynonymous to synonymous substitutions (omega) distinguishes neutrally evolving sequences (omega = 1) from those subjected to purifying (omega < 1) or positive Darwinian (omega > 1) selection. We show that current models used to estimate omega are substantially biased by naturally occurring sequence compositions. We present a novel model that weights substitutions by conditional nucleotide frequencies and which escapes these artifacts. Applying it to the genomes of pathogens causing malaria, leprosy, tuberculosis, and Lyme disease gave significant discrepancies in estimates with approximately 10-30% of genes affected. Our work has substantial implications for how vaccine targets are chosen and for studying the molecular basis of adaptive evolution.
authors.affiliation: Department of Statistics and Applied Probability, National University of Singapore, Singapore, Singapore. stayapvb@nus.edu.sg
authors.forename: Von Bing
authors.initials: VB
authors.lastname: Yap
authors.forename: Helen
authors.initials: H
authors.lastname: Lindsay
authors.forename: Simon
authors.initials: S
authors.lastname: Easteal
authors.forename: Gavin
authors.initials: G
authors.lastname: Huttley
mesh_terms: D001482:Base Composition; D016009:Chi-Square Distribution; D003062:Codon; D003198:Computer Simulation; D019143:Evolution, Molecular; D017125:Genes, Protozoan; D008957:Models, Genetic; D015233:Models, Statistical; D009154:Mutation; D010961:Plasmodium / Q000235:genetics; D012641:Selection, Genetic; D016415:Sequence Alignment
chemical_list: D003062:Codon