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Patterns of de novo tandem repeat mutations and their role in autism

Author

Listed:
  • Ileena Mitra

    (University of California San Diego)

  • Bonnie Huang

    (University of California San Diego)

  • Nima Mousavi

    (University of California San Diego)

  • Nichole Ma

    (University of California San Diego)

  • Michael Lamkin

    (University of California San Diego)

  • Richard Yanicky

    (University of California San Diego)

  • Sharona Shleizer-Burko

    (University of California San Diego)

  • Kirk E. Lohmueller

    (University of California Los Angeles
    University of California Los Angeles)

  • Melissa Gymrek

    (University of California San Diego
    University of California San Diego)

Abstract

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.

Suggested Citation

  • Ileena Mitra & Bonnie Huang & Nima Mousavi & Nichole Ma & Michael Lamkin & Richard Yanicky & Sharona Shleizer-Burko & Kirk E. Lohmueller & Melissa Gymrek, 2021. "Patterns of de novo tandem repeat mutations and their role in autism," Nature, Nature, vol. 589(7841), pages 246-250, January.
  • Handle: RePEc:nat:nature:v:589:y:2021:i:7841:d:10.1038_s41586-020-03078-7
    DOI: 10.1038/s41586-020-03078-7
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    Citations

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    Cited by:

    1. Xiaoyu Shan & Rachel E. Szabo & Otto X. Cordero, 2023. "Mutation-induced infections of phage-plasmids," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Frank R. Wendt & Gita A. Pathak & Renato Polimanti, 2022. "Phenome-wide association study of loci harboring de novo tandem repeat mutations in UK Biobank exomes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Snaedis Kristmundsdottir & Hakon Jonsson & Marteinn T. Hardarson & Gunnar Palsson & Doruk Beyter & Hannes P. Eggertsson & Arnaldur Gylfason & Gardar Sveinbjornsson & Guillaume Holley & Olafur A. Stefa, 2023. "Sequence variants affecting the genome-wide rate of germline microsatellite mutations," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    4. Kazuki Ichikawa & Riki Kawahara & Takeshi Asano & Shinichi Morishita, 2023. "A landscape of complex tandem repeats within individual human genomes," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Yirong Shi & Yiwei Niu & Peng Zhang & Huaxia Luo & Shuai Liu & Sijia Zhang & Jiajia Wang & Yanyan Li & Xinyue Liu & Tingrui Song & Tao Xu & Shunmin He, 2023. "Characterization of genome-wide STR variation in 6487 human genomes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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