Measuring Intolerance to Mutation in Human Genetics

Overview

Journal Nat Genet

Specialty Genetics

Date 2019 Apr 10

PMID 30962618

Citations 64

Authors

Zachary L Fuller

Jeremy J Berg

Hakhamanesh Mostafavi

Guy Sella

Molly Przeworski

Affiliations

Soon will be listed here.

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.

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