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A phylogenetic approach to assessing the significance of missense mutations in disease genes
Author(s) -
Koref M.F. Santibáñez,
Gangeswaran R.,
Koref I.P. Santibáñez,
Shanahan N.,
Hancock J.M.
Publication year - 2003
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.10235
Subject(s) - biology , missense mutation , genetics , phylogenetic tree , gene , mutation , conserved sequence , computational biology , peptide sequence
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. Hum Mutat 22:51–58, 2003. © 2003 Wiley‐Liss, Inc.