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A phylogenetic approach to assessing the significance of missense mutations in disease genes

✍ Scribed by M.F. Santibáñez Koref; R. Gangeswaran; I.P. Santibáñez Koref; N. Shanahan; J.M. Hancock

Publisher
John Wiley and Sons
Year
2003
Tongue
English
Weight
246 KB
Volume
22
Category
Article
ISSN
1059-7794

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✦ Synopsis

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.

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