Phylomedicine: an evolutionary telescope to explore and diagnose the universe of disease mutations

Modern technologies have made the sequencing of personal genomes routine. They have revealed thousands of nonsynonymous (amino acid altering) single nucleotide variants (nSNVs) of protein-coding DNA per genome. What do these variants foretell about an individual's predisposition to diseases? The experimental technologies required to carry out such evaluations at a genomic scale are not yet available. Fortunately, the process of natural selection has lent us an almost infinite set of tests in nature. During long-term evolution, new mutations and existing variations have been evaluated for their biological consequences in countless species, and outcomes are readily revealed by multispecies genome comparisons. We review studies that have investigated evolutionary characteristics and in silico functional diagnoses of nSNVs found in thousands of disease-associated genes. We conclude that the patterns of long-term evolutionary conservation and permissible sequence divergence are essential and instructive modalities for functional assessment of human genetic variations.