Bioinformatics Advance Access originally published online on September 3, 2009
Bioinformatics 2009 25(21):2744-2750; doi:10.1093/bioinformatics/btp528
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Automated inference of molecular mechanisms of disease from amino acid substitutions
1 School of Informatics and Computing, Indiana University, Bloomington, IN 47408, 2 Buck Institute for Age Research, Novato, CA 94945, 3 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA and 4 Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
* To whom correspondence should be addressed.
 |
Abstract |
|---|
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 
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{at}indiana.edu; smooney{at}buckinstitute.org
Associate Editor: Burkhard Rost
Received on May 29, 2009; revised on August 10, 2009; accepted on September 1, 2009
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. G. Kann Advances in translational bioinformatics: computational approaches for the hunting of disease genes Brief Bioinform, January 1, 2010; 11(1): 96 - 110. [Abstract] [Full Text] [PDF]
|
|