TY - GEN
T1 - A probabilistic method to identify compensatory substitutions for pathogenic mutations
AU - Easton, B. C.
AU - Isaev, A. V.
AU - Huttley, G. A.
AU - Maxwell, P.
PY - 2007
Y1 - 2007
N2 - Complex systems of interactions govern the structure and function of biomolecules. Mutations that substantially disrupt these interactions are deleterious and should not persist under selection. Yet, several instances have been reported where a variant confirmed as pathogenic in one species is fixed in the orthologs of other species. Here we introduce a novel method for detecting compensatory substitutions for these so-called compensated pathogenic deviations (CPDs), incorporating knowledge of pathogenic variants into a probabilistic method for detecting correlated evolution. The success of this approach is demonstrated for 26 of 31 CPDs observed in mitochondrial transfer RNAs and for one in beta hemoglobin. The detection of multiple compensatory sites is demonstrated for two of these CPDs. The methodology is applicable to comparative sequence data for biomolecules expressed in any alphabet, real or abstract. It provides a widely applicable approach to the prediction of compensatory substitutions for CPDs, avoiding any reliance on rigid non-probabilistic criteria or structural data. The detection of compensatory substitutions that facilitate the substitution of otherwise pathogenic variants offers valuable insight into the molecular constraints imposed on adaptive evolution.
AB - Complex systems of interactions govern the structure and function of biomolecules. Mutations that substantially disrupt these interactions are deleterious and should not persist under selection. Yet, several instances have been reported where a variant confirmed as pathogenic in one species is fixed in the orthologs of other species. Here we introduce a novel method for detecting compensatory substitutions for these so-called compensated pathogenic deviations (CPDs), incorporating knowledge of pathogenic variants into a probabilistic method for detecting correlated evolution. The success of this approach is demonstrated for 26 of 31 CPDs observed in mitochondrial transfer RNAs and for one in beta hemoglobin. The detection of multiple compensatory sites is demonstrated for two of these CPDs. The methodology is applicable to comparative sequence data for biomolecules expressed in any alphabet, real or abstract. It provides a widely applicable approach to the prediction of compensatory substitutions for CPDs, avoiding any reliance on rigid non-probabilistic criteria or structural data. The detection of compensatory substitutions that facilitate the substitution of otherwise pathogenic variants offers valuable insight into the molecular constraints imposed on adaptive evolution.
UR - http://www.scopus.com/inward/record.url?scp=60849115679&partnerID=8YFLogxK
U2 - 10.1142/9781860947995_0022
DO - 10.1142/9781860947995_0022
M3 - Conference contribution
SN - 9781860947834
T3 - Series on Advances in Bioinformatics and Computational Biology
SP - 195
EP - 204
BT - Proceedings of the 5th Asia-Pacific Bioinformatics Conference, APBC 2007
PB - Imperial College Press
T2 - 5th Asia-Pacific Bioinformatics Conference, APBC 2007
Y2 - 15 January 2007 through 17 January 2007
ER -