Genome-wide patterns ofde novotandem repeat mutations and their contribution to autism spectrum disorders
| Autor: | Bonnie Huang, Kirk E. Lohmueller, Michael Lamkin, Nichole Ma, Nima Mousavi, Ileena Mitra, Melissa Gymrek, Richard Yanicky, Sharona Shleizer-Burko |
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| Rok vydání: | 2020 |
| Předmět: |
Whole genome sequencing
Proband Genetics 0303 health sciences Mutation Biology medicine.disease medicine.disease_cause Genome Developmental disorder 03 medical and health sciences 0302 clinical medicine Tandem repeat Autism spectrum disorder medicine Autism 030217 neurology & neurosurgery 030304 developmental biology |
| Popis: | Autism Spectrum Disorder (ASD) is an early onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviors1,2. Family studies demonstrate that ASD has a significant genetic basis3with contributions both from inherited andde novovariants. While the majority of variance in liability to ASD is estimated to arise from common genetic variation4, it has been estimated thatde novomutations may contribute to 30% of all simplex cases, in which only a single child is affected per family5. Tandem repeats (TRs), consisting of approximately 1-20bp motifs repeated in tandem, comprise one of the largest sources ofde novomutations in humans6. Yet, largely due to technical challenges they present,de novoTR mutations have not yet been characterized on a genome-wide scale, and their contribution to ASD remains unexplored. Here, we develop novel bioinformatics tools for identifying and prioritizingde novoTR mutations from whole genome sequencing (WGS) data and use these to perform a genome-wide characterization ofde novoTR mutations in ASD-affected probands and unaffected siblings. Compared to recent work on TRs in ASD7, we explicitly infer mutation events and their precise changes in repeat copy number, and primarily focus on more prevalent stepwise copy number changes rather than large or complex expansions. Our results demonstrate a significant genome-wide excess of TR mutations in ASD probands. TR mutations in probands tend to be larger, enriched in fetal brain regulatory regions, and predicted to be more evolutionarily deleterious compared to mutations observed in unaffected siblings. Overall, our results highlight the importance of considering repeat variants in future studies ofde novomutations. |
| Databáze: | OpenAIRE |
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