Figure 1. Current sources of gene intolerance to LoF variation/essentiality and lethal phenotypes.

The phenotypic impact of a gene’s LoF can be assessed in humans at the cellular level, through cell proliferation assays; observed versus expected variation inferred from large scale population sequencing data and evaluation of lethal phenotypes in patients affected by Mendelian conditions. In the mouse, different viability assessment screens allow the identification of homozygous knockouts with preweaning lethal phenotypes. LoF: loss-of-function; ML: machine learning.