Measuring intolerance to mutation in human genetics

By Z. Fuller, Jeremy J. Berg, H. Mostafavi, Guy Sella, M. Przeworski. 2018

129 citations recorded by the source corpus.

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. This Perspective discusses how best to interpret pLI, a measure widely used to identify genes that are intolerant to a single copy of a truncating mutation, by relating this and related measures to the underlying population-genetic theory.

Subfields: Genetics

Citations in the corpus

• Evaluating drug targets through human loss-of-function genetic variation (2019, unknown): “Constraint is believed to primarily reflect selection against heterozygotes 13 , whose effective gene dosage may differ from that achieved by a drug.”