In silico functional profiling of human disease-associated and polymorphic amino acid substitutions.

An important challenge in translational bioinformatics is to understand how genetic variation gives rise to molecular changes at the protein level that can precipitate both monogenic and complex disease. To this end, we compiled datasets of human disease-associated amino acid substitutions (AAS) in the contexts of inherited monogenic disease, complex disease, functional polymorphisms with no known disease association, and somatic mutations in cancer, and compared them with respect to predicted functional sites in proteins. Using the sequence homology-based tool SIFT to estimate the proportion of deleterious AAS in each dataset, only complex disease AAS were found to be indistinguishable from neutral polymorphic AAS. Investigation of monogenic disease AAS predicted to be nondeleterious by SIFT were characterized by a significant enrichment for inherited AAS within solvent accessible residues, regions of intrinsic protein disorder, and an association with the loss or gain of various posttranslational modifications. Sites of structural and/or functional interest were therefore surmised to constitute useful additional features with which to identify the molecular disruptions caused by deleterious AAS. A range of bioinformatic tools, designed to predict structural and functional sites in protein sequences, were then employed to demonstrate that intrinsic biases exist in terms of the distribution of different types of human AAS with respect to specific structural, functional and pathological features. Our Web tool, designed to potentiate the functional profiling of novel AAS, has been made available at http://profile.mutdb.org/.

Automated inference of molecular mechanisms of disease from amino acid substitutions.

MOTIVATION: Advances in high-throughput genotyping and next generation sequencing have generated a vast amount of human genetic variation data. Single nucleotide substitutions within protein coding regions are of particular importance owing to their potential to give rise to amino acid substitutions that affect protein structure and function which may ultimately lead to a disease state. Over the last decade, a number of computational methods have been developed to predict whether such amino acid substitutions result in an altered phenotype. Although these methods are useful in practice, and accurate for their intended purpose, they are not well suited for providing probabilistic estimates of the underlying disease mechanism. RESULTS: We have developed a new computational model, MutPred, that is based upon protein sequence, and which models changes of structural features and functional sites between wild-type and mutant sequences. These changes, expressed as probabilities of gain or loss of structure and function, can provide insight into the specific molecular mechanism responsible for the disease state. MutPred also builds on the established SIFT method but offers improved classification accuracy with respect to human disease mutations. Given conservative thresholds on the predicted disruption of molecular function, we propose that MutPred can generate accurate and reliable hypotheses on the molecular basis of disease for approximately 11% of known inherited disease-causing mutations. We also note that the proportion of changes of functionally relevant residues in the sets of cancer-associated somatic mutations is higher than for the inherited lesions in the Human Gene Mutation Database which are instead predicted to be characterized by disruptions of protein structure. AVAILABILITY: http://mutdb.org/mutpred CONTACT: predrag@indiana.edu; smooney@buckinstitute.org.