Involvement of tissue-specific genes in human diseases and expression specificity across diverse human cell types. a–c) Degree of intolerance to (a) loss-of-function mutations, (b) missense mutations, and (c) synonymous mutations. Values are the Log2 of the ratio between the observed and expected number of mutations for tissue-specific genes and all other genes. P-values were calculated using Wilcoxon signed-rank tests. (d) Ten most significant human phenotypes that are associated with tissue-specific genes. The X-axis represents the number of genes that overlap a specific term. Color intensity signifies the -log (10) of the FDR q-value. e–g) Percentage of genes associated with human diseases. e) Comparing tissue-specific genes, CEGs, and NEGs. f) Comparing disease involvement between tissue-specific genes implicated in 3 universal mechanisms with other tissue-specific genes and CEG. The 3 universal mechanisms, PE, FR, and FC, were treated as 1 group. g) Comparing disease involvement between PE, FR, and FC. h) Proportions of genes with paralogs for tissue-specific genes, CEG, and NEG. i) Association between cell type-specific expression of the tissue-specific gene itself (Gene) or the paralog (Paralog) with genes implicated in PE, FR, FC relative to NEG. Values are ORs ± 95% confidence interval. NS, P > 0.05; *, P < 0.05; **, P < 0.005; ***, P < 0.001.