PT  - JOURNAL ARTICLE
AU  - Fuller, Zachary L.
AU  - Berg, Jeremy J.
AU  - Mostafavi, Hakhamanesh
AU  - Sella, Guy
AU  - Przeworski, Molly
TI  - Measuring Intolerance to Mutation in Human Genetics
AID  - 10.1101/382481
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 382481
4099  - http://biorxiv.org/content/early/2018/08/01/382481.short
4100  - http://biorxiv.org/content/early/2018/08/01/382481.full
AB  - 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 deleterious1–4. 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 mutation3,5–9. One measure in particular, pLI, has been widely adopted7. By contrasting the observed versus expected numbers of PTVs, it aims to classify genes into three categories, labelled null, recessive and haploinsufficient7. 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.