Disease risk of missense mutations using structural inference from predicted function.
Advancements in sequencing techniques place personalized genomic medicine upon the horizon, bringing along the responsibility of clinicians to understand the likelihood for a mutation to cause disease, and of scientists to separate etiology from nonpathologic variability. Pathogenicity is discernable from patterns of interactions between a missense mutation, the surrounding protein structure, and intermolecular interactions. Physicochemical stability calculations are not accessible without structures, as is the case for the vast majority of human proteins, so diagnostic accuracy remains in infancy. To model the effects of missense mutations on functional stability without structure, we combine novel protein sequence analysis algorithms to discern spatial distributions of sequence, evolutionary, and physicochemical conservation, through a new approach to optimize component selection. Novel components include a combinatory substitution matrix and two heuristic algorithms that detect positions which confer structural support to interaction interfaces. The method reaches 0.91 AUC in ten-fold cross-validation to predict alteration of function for 6,392 in vitro mutations. For clinical utility we trained the method on 7,022 disease associated missense mutations within the Online Mendelian inheritance in man amongst a larger randomized set. In a blinded prospective test to delineate mutations unique to 186 patients with craniosynostosis from those in the 95 highly variant Coriell controls and 1000 age matched controls, we achieved roughly 1/3 sensitivity and perfect specificity. The component algorithms retained during machine learning constitute novel protein sequence analysis techniques to describe environments supporting neutrality or pathology of mutations. This approach to pathogenetics enables new insight into the mechanistic relationship of missense mutations to disease phenotypes in our patients.
Horst
Jeremy A
JA
Department of Microbiology School of Medicine, University of Washington, 1959 NE Pacific St 357132, Seattle, WA 98195, USA.
Wang
Kai
K
Horst
Orapin V
OV
Cunningham
Michael L
ML
Samudrala
Ram
R
D000465:Algorithms; D019943:Amino Acid Substitution; D003198:Computer Simulation; D030541:Databases, Genetic; D030562:Databases, Protein; D004194:Disease / Q000235:genetics*; D006801:Humans; D056968:Lac Repressors / Q000737:chemistry*; D008390:Markov Chains; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry*; D020125:Mutation, Missense; D016571:Neural Networks, Computer; D020641:Polymorphism, Single Nucleotide; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D018570:Risk Assessment; D012307:Risk Factors; D016415:Sequence Alignment
D056968:Lac Repressors; D050505:Mutant Proteins