Functional Metrics for Various Gene Sets Derived from CNV and SNV Studies, as well as HI Scores for Genic Deletions
(A) Box plots of pHIs for various genes sets. Boxes correspond to the spread between the upper and lower quartiles; medians are indicated by a solid horizontal line, and whiskers extend up to 1.5× the interquartile range. “Genome” indicates all 16,781 genes with an available pHI from an imputed data set, excluding seed genes. Only genes implicated in dominant, recessive, or X-linked disorders with neurological phenotypes in the HPO database (“HPO het,” “HPO hom,” “HPO X,” respectively) and mouse genes whose homozygous, heterozygous, or X-linked knockout (“MPO het,” “MPO hom,” “MPO X,” respectively) causes various abnormal phenotypes were considered. The median pHI for HPO het was selected as the threshold to differentiate between dominant and recessive genes (red horizontal line). Genes implicated in ASD and ID were further annotated into dominant (dom), recessive (rec), or X-linked (XL) genes. Other abbreviations are as follows: dn, de novo; allg; all genes; DEL, deletion; “1g-NBG 69g,” 69 genes selected by NETBAG analysis of 102 de novo CNVs with up to one gene per each CNV region; “2g-NBG 113g,” 113 genes selected by NETBAG analysis with up to two genes per CNV (as depicted in Figure 4B); “2g-NBG DEL/disr 80g,” subset of NETBAG genes completely overlapped or disrupted by deletions (no duplications were considered); “ASD (CompStudies) dn SNV 122g,” 122 genes affected by de novo LoF SNVs from ASD exome sequencing studies; “ID (CompStudies) dn SNV 32g,” 32 genes affected by de novo LoF SNVs from ID exome sequencing studies; “SCZ (Xu2012) dn SNV 22g,” 22 genes affected by de novo LoF SNVs from schizophrenia exome sequencing studies; “ASD (Lim2013) rec SNV 49g,” 49 genes affected by hemizygous LoF SNVs on the X chromosome of ASD males; “ID (Najmabadi2011) rec SNV 73g,” 73 genes hit by recessive SNVs in consanguineous ID-affected families; “pre-DAPPLE ASD input 336g,” 336 DAPPLE input genes; “336g minus 151g excluded 185g,” 185 genes not used by DAPPLE; “DAPPLE ASD direct-PPI 151g,” 151 genes depicted in the network of Figure 5B; “DAPPLE minus 54 known genes 97g,” 97 genes depicted in the network of Figure 5B (and listed in Table S16), not including the 54 genes previously implicated in ASD (yellow nodes); and “DAPPLE known genes only 54g,” 54 genes known to be involved in ASD.
(B) LOD scores of the probability that at least one gene within a rare deletion will cause haploinsufficiency were calculated for affected and control subjects. Deletion-based LOD scores are plotted as a function of the number of genes in each event for rare genic deletions in affected and control subjects. The p value for the difference in the slope of the two regression lines is indicated.
(C) Box plots with the distribution of predicted functional indispensability scores for gene categories from Khurana et al.55 (LoF-tolerant genes, neutral genes, genes with known mutations as listed in the Human Genome Mutation Database, and essential genes [i.e., genes in which LoF mutations result in infertility or death before puberty]) and CNV or SNV genes from our DAPPLE analysis (185 genes excluded by DAPPLE, 151 genes selected by DAPPLE, 54 known ASD-implicated genes selected by DAPPLE, and 97 genes selected by DAPPLE after exclusion of the 54 ASD-implicated genes).
(D) Box plots with the distributions of degree centrality in Multinet55 for the same gene categories as in (C).
(E) Box plots with the distributions of the number of networks in which a gene is involved in Multinet for the same gene categories as in (C) and (D).