title: A phylogenetic approach to assessing the significance of missense mutations in disease genes.
abstract: The identification of deleterious mutations within candidate genes is a crucial step in the elucidation of the genetic bases of human disease. However, the significance of any base or amino acid change within a gene is unknown until detailed structural and functional analysis has been carried out. A potentially rapid way of identifying functionally important sites within a gene is to identify evolutionarily conserved regions. Mutations affecting such sites are assumed to be deleterious for the carrier. In this communication we generalize this approach and present a formal framework to assess whether a specific mutation is deleterious given sequence data from a set of homologues. We propose a score that takes into account the nature of the mutation, the conservation of the affected residue among the different species, and their phylogenetic relationships. Its performance is examined using published TP53 mutations and frequent polymorphic variants.
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany.
authors.forename: M F
authors.initials: MF
authors.lastname: Santibáñez Koref
authors.forename: R
authors.initials: R
authors.lastname: Gangeswaran
authors.forename: I P
authors.initials: IP
authors.lastname: Santibáñez Koref
authors.forename: N
authors.initials: N
authors.lastname: Shanahan
authors.forename: J M
authors.initials: JM
authors.lastname: Hancock
mesh_terms: D019295:Computational Biology / Q000379:methods / Q000706:statistics & numerical data; D004252:DNA Mutational Analysis / Q000379:methods / Q000706:statistics & numerical data; D030541:Databases, Genetic / Q000706:statistics & numerical data; D019143:Evolution, Molecular; D005787:Gene Frequency / Q000235:genetics; D005796:Genes / Q000235:genetics*; D016158:Genes, p53 / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D008957:Models, Genetic; D020125:Mutation, Missense; D010802:Phylogeny; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000145:classification / Q000235:genetics
chemical_list: D016159:Tumor Suppressor Protein p53