A Method to Delineate De Novo Missense Variants Across Pathways Prioritizes Genes Linked to Autism

Authors

Amanda Koire
Panagiotis Katsonis
Young Won Kim
Christie Buchovecky
Stephen J Wilson
Olivier Lichtarge

Publication Date

5-19-2021

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.abc1739

PMID

34011629

PMCID

PMC8916821

PubMedCentral® Posted Date

3-11-2022

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Autism Spectrum Disorder, Autistic Disorder, Exome, Genetic Predisposition to Disease, Humans, Phenotype, Phylogeny

Abstract

Genotype-phenotype relationships shape health and population fitness but remain difficult to predict and interpret. Here, we apply an evolutionary action method in mutational landscapes to unravel genes and pathways connected to autism spectrum disorder (ASD). Evolutionary action predicts the impact of missense variants on protein function by measuring motions in fitness landscapes, based on phylogenetic distances and substitution odds in homologous sequences. By examining 368 pathways across 2,384 individuals with ASD (probands), we found that 23 pathways, a total of 398 genes, had de novo missense variants biased to higher evolutionary action scores than expected by random chance, including axonogenesis, synaptic transmission, and neurodevelopmental pathways. The predicted fitness impact of de novo and inherited missense variants in candidate genes correlated with the IQ of individuals with ASD, even for using only the new gene candidates. This approach demonstrates how the evolutionary action method can be applied in biology to integrate missense variants over a cohort to identify genes contributing a shared phenotype. Using this approach, we have detected those missense variants most likely to contribute to ASD pathogenesis and have elucidated their phenotypic impact.

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