Correlated Mutations: A Hallmark of Phenotypic Amino Acid Substitutions

Point mutations resulting in the substitution of a single amino acid can cause severe functional consequences, but can also be completely harmless. Understanding what determines the phenotypical impact is important both for planning targeted mutation experiments in the laboratory and for analyzing naturally occurring mutations found in patients. Common wisdom suggests using the extent of evolutionary conservation of a residue or a sequence motif as an indicator of its functional importance and thus vulnerability in case of mutation. In this work, we put forward the hypothesis that in addition to conservation, co-evolution of residues in a protein influences the likelihood of a residue to be functionally important and thus associated with disease. While the basic idea of a relation between co-evolution and functional sites has been explored before, we have conducted the first systematic and comprehensive analysis of point mutations causing disease in humans with respect to correlated mutations. We included 14,211 distinct positions with known disease-causing point mutations in 1,153 human proteins in our analysis. Our data show that (1) correlated positions are significantly more likely to be disease-associated than expected by chance, and that (2) this signal cannot be explained by conservation patterns of individual sequence positions. Although correlated residues have primarily been used to predict contact sites, our data are in agreement with previous observations that (3) many such correlations do not relate to physical contacts between amino acid residues. Access to our analysis results are provided at http://webclu.bio.wzw.tum.de/~pagel/supp​lements/correlated-positions/. Point mutations (i.e., changes of a single sequence element) can have a severe impact on protein function. Many diseases are caused by such minute defects. On the other hand, the majority of such mutations does not lead to noticeable effects. Although previous research has revealed important aspects that influence or predict the chance of a mutation to cause disease, much remains to be learned before we fully understand this complex problem. In our work, we use the observation that sometimes certain positions in a protein mutate in an apparently correlated fashion and analyze this correlation with respect to mutation vulnerability. Our results show that positions exhibiting evolutionary correlation are significantly more likely to be vulnerable to mutation than average positions. On one hand, our data further support the concept of correlated positions to not only be associated with protein contacts but also functional sites and/or disease positions (as introduced by others). On the other hand, this could be useful to further improve the understanding and prediction of the consequences of mutations. Our work is the first to attempt a large-scale quantitation of this relationship.