Patterns of de novo tandem repeat mutations and their role in autism
Autor: | Melissa Gymrek, Bonnie Huang, Michael Lamkin, Ileena Mitra, Richard Yanicky, Nichole Ma, Nima Mousavi, Kirk E. Lohmueller, Sharona Shleizer-Burko |
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Rok vydání: | 2021 |
Předmět: |
Proband
Adult Male Adolescent DNA Copy Number Variations Base pair Autism Spectrum Disorder General Science & Technology Intellectual and Developmental Disabilities (IDD) Autism Biology medicine.disease_cause Article Paternal Age 03 medical and health sciences Young Adult 0302 clinical medicine Fetus Tandem repeat Genetic variation medicine Genetics 2.1 Biological and endogenous factors Humans Genetic Predisposition to Disease Least-Squares Analysis Child Germ-Line Mutation 030304 developmental biology Pediatric 0303 health sciences Mutation Multidisciplinary DNA Repeat Expansion Human Genome Neurosciences Brain Middle Aged medicine.disease Brain Disorders Developmental disorder Mental Health Autism spectrum disorder Female 030217 neurology & neurosurgery |
Zdroj: | Nature, vol 589, iss 7841 Nature |
Popis: | Autism spectrum disorder (ASD) is an early-onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviours1,2. Family studies demonstrate that ASD has a substantial genetic basis with contributions both from inherited and de novo variants3,4. It has been estimated that de novo mutations may contribute to 30% of all simplex cases, in which only a single child is affected per family5. Tandem repeats (TRs), defined here as sequences of 1 to 20 base pairs in size repeated consecutively, comprise one of the major sources of de novo mutations in humans6. TR expansions are implicated in dozens of neurological and psychiatric disorders7. Yet, de novo TR mutations have not been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here we develop new bioinformatics methods for identifying and prioritizing de novo TR mutations from sequencing data and perform a genome-wide characterization of de novo TR mutations in ASD-affected probands and unaffected siblings. We infer specific mutation events and their precise changes in repeat number, and primarily focus on more prevalent stepwise copy number changes rather than large expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. Mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and are predicted to be more evolutionarily deleterious. Overall, our results highlight the importance of considering repeat variants in future studies of de novo mutations. A bioinformatics pipeline to identify tandem repeat mutations is developed and used to characterize precise changes in repeat copy number associated with autism spectrum disorder. |
Databáze: | OpenAIRE |
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