It has been appreciated for some time that the distribution of minor allele frequencies (MAFs) is strongly skewed towards an excess of rare variants: over a third of all polymorphisms have frequencies below 5%31. Multiple factors contribute to this skewed distribution, but the finding from whole-exome sequence data that non-synonymous substitutions are even more significantly skewed towards low frequencies almost certainly reflects the operation of purifying selection32–34. As a class, amino acid substitutions appear to be deleterious. It need not follow that the reduction in fitness is due to promotion of chronic disease, and the observation does not equate to saying that all rare non-synonymous variants are deleterious. However, the finding is consistent with the theory that selection keeps fitness-reducing alleles at a large proportion of genes at low frequency35. It remains to be seen whether the same is true of regulatory polymorphisms36,37, since (despite the considerable technological achievements of the ENCODE project, http://www.genome.gov/10005107) we still lack efficient procedures for identifying enhancers and other regulatory regions that polymorphisms could disrupt38.
