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Measuring "intolerance to mutation" in human genetics

By Zachary Fuller, Jeremy J. Berg, Hakhamanesh Mostafavi, Guy Sella, Molly Przeworski

Posted 01 Aug 2018
bioRxiv DOI: 10.1101/382481 (published DOI: 10.1038/s41588-019-0383-1)

In numerous applications, from working with animal models to mapping the genetic basis of human disease susceptibility, it is useful to know whether a single disrupting mutation in a gene is likely to be deleterious. 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 numbers of healthy individuals--genes that appear "intolerant to mutation". One measure in particular, pLI, has been widely adopted. By contrasting the observed versus expected number of PTVs, it aims to classify genes into three categories, labelled "null", "recessive" and "haploinsufficient". Here we discuss how pLI and similar measures relate to population genetic parameters and why they reflect the strength of selection acting on heterozygotes, rather than dominance or haploinsufficiency.

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