Measuring intolerance to mutation in human genetics


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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Fig. 1: pLI relates to hs, but not h and s separately.
Fig. 2: Properties of pLI.

Data availability

C++ source code for the simulations of PTV counts and accompanying scripts used for plotting and data analysis are available at


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We thank A. Chakravarti, G. Coop, M. B. Eisen, M. Hurles, J. K. Pritchard, Y. Shen and members of the laboratories of M. Przeworski and G. Sella for helpful discussions. This work was supported by GM128318 to Z.L.F., GM126787 to J.J.B., GM121372 to M.P. and GM115889 to G.S. We acknowledge computing resources from Columbia University's Shared Research Computing Facility project, which is supported by NIH Research Facility Improvement Grant 1G20RR030893-01, and associated funds from the New York State Empire State Development, Division of Science Technology and Innovation (NYSTAR) contract C090171.

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All authors conceived and designed the project. M.P. and G.S. supervised the study. Z.L.F. performed simulations. H.M., J.J.B. and Z.L.F. led the data analysis. All authors wrote the manuscript and approved the final version.

Correspondence to Zachary L. Fuller.

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