(observed ≈ expected), recessive (observed ≤50% of expected), and haploinsufficient (observed <10% of expected). This metric – the probability of being loss-of-function (LoF) intolerant (pLI) – separates genes of sufficient length into LoF intolerant (pLI ≥0.9, n=3,230) or LoF tolerant (pLI ≤0.1, n=10,374) categories. pLI is less correlated with coding sequence length (r = 0.17 as compared to 0.57 for the PTV Z score), outperforms the PTV Z score as an intolerance metric (Supplementary Information Table 15), and reveals the expected contrast between gene lists (Figure 3b). pLI is positively correlated with a gene product’s number of physical interaction partners (p < 10−41). The most constrained pathways (highest median pLI for the genes in the pathway) are core biological processes (spliceosome, ribosome, and proteasome components; KS test p < 10−6 for all) while olfactory receptors are among the least constrained pathways (KS test p < 10−16), demonstrated in Figure 3b and consistent with previous work5,16–19.
