Evolutionary diagnosis method for variants in personal exomes

Kumar, S., Sanderford, M., Gray, V. E., Ye, J., & Liu, L. (2012). . [10.1038/nmeth.2147]. Nat Meth, 9(9), 855-856. (not open access)

Abstract: Each human exome contains thousands of nonsynonymous single-nucleotide variants (nSNVs) that have unknown biological effects. The potential impact of nSNVs on biological function is now routinely assessed using computational methods for application in biomedical research and clinical genome profiling reports. Of the variants receiving a non-neutral (function-damaging) prediction, those at evolutionarily conserved sites are frequently of heightened interest for scientists and clinicians because such sites are among the most critical for proper protein function. Indeed, a majority of amino acid mutations that have been investigated experimentally are located at ultraconserved sites¹, which show no amino acid residue difference among diverse species spanning over 500 million years of evolution (Supplementary Fig. 1). Functionally damaging mutants at these sites are likely to have significant consequences for health and disease.