What your genome won't tolerate
/This is one of those projects that’s so clearly interesting and important that it’s surprising nobody has done it already: specifically, this is a very thorough and well-executed analysis of all the places in the human genome that do not appear to tolerate being mutated. If you have access, it’s worth reading. —RPR
Measuring intolerance to mutation in human genetics
Zachary L. Fuller, Jeremy J. Berg, Hakhamanesh Mostafavi, Guy Sella & Molly Przeworski
Nature Genetics (Research Article)
Abstract—In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, knowing whether a single disrupting mutation in a gene is likely to be deleterious is useful. With this goal in mind, a number of measures have been developed to identify genes in which protein-truncating variants (PTVs), or other types of mutations, are absent or kept at very low frequency in large population samples—genes that appear ‘intolerant’ to mutation. One measure in particular, the probability of being loss-of-function intolerant (pLI), has been widely adopted. This measure was designed to classify genes into three categories, null, recessive and haploinsufficient, on the basis of the contrast between observed and expected numbers of PTVs. Such population-genetic approaches can be useful in many applications. As we clarify, however, they reflect the strength of selection acting on heterozygotes and not dominance or haploinsufficiency.
