Figure 2.

Estimated Number of Genes for Mendelian Conditions

(A) Priority candidate genes for Mendelian conditions (MCs) yet to be discovered or delineated can be identified based on detecting a deficit of variation in healthy human controls due to purifying selection (i.e., human data) or the existence of at least one mutant mouse line with an abnormal phenotype (i.e., mouse data). Each stacked bar illustrates, from left to right, the number of human genes known to underlie an MC but not supported by a given type of evidence (dark blue); known to underlie an MC and supported by evidence (light blue); not known to underlie an MC (i.e., novel) and not supported by evidence (burnt orange); and not known to underlie an MC but evidence suggests that it does and it is therefore a priority candidate gene (bright orange) supported by evidence. Selecting the intersection of genes supported by both mouse and human data yields 4,450 priority candidate genes that are likely to underlie one or more novel MCs.

(B) Alternatively, the union of genes supported by either mouse or human data suggests there are at least 10,467 priority candidate genes likely to underlie one or more new MCs. Both of these estimates are probably conservative for several reasons: ∼25% of genes underlie two or more distinct MCs (adjusting for this yields ∼6,100–14,400 potential novel MCs), mutant phenotypes for >12,000 mouse genes have not yet been assessed, and current human constraint metrics still lack power to detect constraint in ∼30% of all genes and are underpowered to detect constraint against homozygous loss of function. (See Supplemental Data for details.)