Unified inference of missense variant effects and gene constraints in the human genome

Abstract

A challenge in medical genomics is to identify variants and genes associated with severe genetic disorders. Based on the premise that severe, early-onset disorders often result in a reduction of evolutionary fitness, several statistical methods have been developed to predict pathogenic variants or constrained genes based on the signatures of negative selection in human populations. However, we currently lack a statistical framework to jointly predict deleterious variants and constrained genes from both variant-level features and gene-level selective constraints. Here we present such a unified approach, UNEECON, based on deep learning and population genetics. UNEECON treats the contributions of variant-level features and gene-level constraints as a variant-level fixed effect and a gene-level random effect, respectively. The sum of the fixed and random effects is then combined with an evolutionary model to infer the strength of negative selection at both variant and gene levels. Compared with previously published methods, UNEECON shows unmatched performance in predicting missense variants and protein-coding genes associated with autosomal dominant disorders, and feature importance analysis suggests that both gene-level selective constraints and variant-level predictors are important for accurate variant prioritization. Furthermore, based on UNEECON, we observe an unexpected low correlation between gene-level intolerance to missense mutations and that to loss-of-function mutations, which can be partially explained by the prevalence of disordered protein regions that are highly tolerant to missense mutations. Finally, we show that genes intolerant to both missense and loss-of-function mutations play key roles in the central nervous system and the autism spectrum disorders. Overall, UNEECON is a promising framework for both variant and gene prioritization.\n\nAuthor summaryNumerous statistical methods have been developed to predict deleterious missense variants or constrained genes in the human genome, but unified prioritization methods that utilize both variant- and gene-level information are underdeveloped. Here we present UNEECON, an evolution-based deep learning framework for unified variant and gene prioritization. By integrating variant-level predictors and gene-level selective constraints, UNEECON outperforms existing methods in predicting missense variants and protein-coding genes associated with dominant disorders. Based on UNEECON, we show that disordered proteins are tolerant to missense mutations but not to loss-of-function mutations. In addition, we find that genes under strong selective constraints at both missense and loss-of-function levels are strongly associated with the central nervous system and the autism spectrum disorders, highlighting the need to investigate the function of these highly constrained genes in future studies.