A Method to Delineate De novo Missense Variants across Pathways Prioritizes Genes Linked to Autism
| Autor: | Stephen J. Wilson, Panagiotis Katsonis, Young Won Kim, Christie M. Buchovecky, Amanda Koire, Olivier Lichtarge |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proband
Genetics education.field_of_study Candidate gene Autism Spectrum Disorder Population General Medicine Biology medicine.disease Phenotype Axonogenesis Article mental disorders medicine Missense mutation Autism Humans Exome Genetic Predisposition to Disease Autistic Disorder education Gene Phylogeny |
| Zdroj: | Sci Transl Med |
| Popis: | Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method to de novo missense variants in whole-exome sequences of individuals with autism spectrum disorder (ASD) to unravel genes and pathways connected to ASD. Evolutionary action predicts the impact of missense variants on protein function by measuring the fitness effect based on phylogenetic distances and substitution odds in homologous gene sequences. By examining de novo missense variants in 2384 individuals with ASD (probands) compared to matched siblings without ASD, we found missense variants in 398 genes representing 23 pathways that were biased toward higher evolutionary action scores than expected by random chance; these pathways were involved in axonogenesis, synaptic transmission, and neurodevelopment. The predicted fitness impact of de novo and inherited missense variants in candidate genes correlated with the IQ of individuals with ASD, even for new gene candidates. Taking an evolutionary action method, we detected those missense variants most likely to contribute to ASD pathogenesis and elucidated their phenotypic impact. This approach could be applied to integrate missense variants across a patient cohort to identify genes contributing to a shared phenotype in other complex diseases. |
| Databáze: | OpenAIRE |
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