Environmental carcinogens disproportionally mutate genes implicated in neurodevelopmental disorders

Abstract

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IntroductionDe novo mutations contribute to a large proportion of sporadic psychiatric and developmental disorders, yet the potential role of environmental carcinogens as drivers of causal de novo mutations in neurodevelopmental disorders is poorly studied.MethodsTo explore environmental mutation vulnerability of disease-associated gene sets, we analyzed publicly available whole genome sequencing datasets of mutations in human induced pluripotent stem cell clonal lines exposed to 12 classes of environmental carcinogens, and human lung cancers from individuals living in highly polluted regions. We compared observed rates of exposure-induced mutations in disease-related gene sets with the expected rates of mutations based on control genes randomly sampled from the genome using exact binomial tests. To explore the role of sequence characteristics in mutation vulnerability, we modeled the effects of sequence length, gene expression, and percent GC content on mutation rates of entire genes and gene coding sequences using multivariate Quasi-Poisson regressions.ResultsWe demonstrate that several mutagens, including radiation and polycyclic aromatic hydrocarbons, disproportionately mutate genes related to neurodevelopmental disorders including autism spectrum disorders, schizophrenia, and attention deficit hyperactivity disorder. Other disease genes including amyotrophic lateral sclerosis, Alzheimer’s disease, congenital heart disease, orofacial clefts, and coronary artery disease were generally not mutated more than expected. Longer sequence length was more strongly associated with elevated mutations in entire genes compared with mutations in coding sequences. Increased expression was associated with decreased coding sequence mutation rate, but not with the mutability of entire genes. Increased GC content was associated with increased coding sequence mutation rates but decreased mutation rates in entire genes.DiscussionOur findings support the possibility that neurodevelopmental disorder genetic etiology is partially driven by a contribution of environment-induced germ line and somatic mutations.

Keywords

• somatic mutation
• mutagenesis
• de novo mutation
• carcinogen
• neurodevelopmental disorders
• autism