أرقام وإحصاءات

Insights into DNA repeat expansions among 900,000 biobank paicipants


  • Depienne, C. & Mandel, J.-L. 30 years of repeat expansion disorders: what have we learned and what are the remaining challenges? Am. J. Hum. Genet. 108, 764–785 (2021).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Hannan, A. J. Tandem repeats mediating genetic plasticity in health and disease. Nat. Rev. Genet. 19, 286–298 (2018).

    Article
    CAS
    PubMed

    Google Scholar

  • Ziaei Jam, H. et al. A deep population reference panel of tandem repeat variation. Nat. Commun. 14, 6711 (2023).

    Article
    ADS
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • English, A. C. et al. Analysis and benchmarking of small and large genomic variants across tandem repeats. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02225-z (2024).

    Article
    PubMed
    PubMed Central

    Google Scholar

  • Fotsing, S. F. et al. The impact of short tandem repeat variation on gene expression. Nat. Genet. 51, 1652–1659 (2019).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Margoliash, J. et al. Polymorphic short tandem repeats make widespread contributions to blood and serum traits. Cell Genom. 3, 100458 (2023).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Manigbas, C. A. et al. A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank. Nat. Commun. 15, 10521 (2024).

    Article
    ADS
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Mitra, I. et al. Patterns of de novo tandem repeat mutations and their role in autism. Nature 589, 246–250 (2021).

    Article
    ADS
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Kristmundsdottir, S. et al. Sequence variants affecting the genome-wide rate of germline microsatellite mutations. Nat. Commun. 14, 3855 (2023).

    Article
    ADS
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Porubsky, D. et al. Human de novo mutation rates from a four-generation pedigree reference. Nature 643, 427–436 (2025).

    Article
    ADS
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Gymrek, M., Willems, T., Reich, D. & Erlich, Y. Interpreting short tandem repeat variations in humans using mutational constraint. Nat. Genet. 49, 1495–1501 (2017).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Steely, C. J., Watkins, W. S., Baird, L. & Jorde, L. B. The mutational dynamics of short tandem repeats in large, multigenerational families. Genome Biol. 23, 253 (2022).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Rajagopal, S., Donaldson, J., Flower, M., Hensman Moss, D. J. & Tabrizi, S. J. Genetic modifiers of repeat expansion disorders. Emerg. Top. Life Sci. 7, 325–337 (2023).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell 162, 516–526 (2015).

    Article

    Google Scholar

  • Lee, J.-M. et al. A modifier of Huntington’s disease onset at the MLH1 locus. Hum. Mol. Genet. 26, 3859–3867 (2017).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. CAG repeat not polyglutamine length determines timing of Huntington’s disease onset. Cell 178, 887–900 (2019).

    Article

    Google Scholar

  • Lee, J.-M. et al. Genetic modifiers of Huntington disease differentially influence motor and cognitive domains. Am. J. Hum. Genet. 109, 885–899 (2022).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease highlight shared and tissue-specific effects. Nat. Genet. 57, 1426–1436 (2025).

    Article

    Google Scholar

  • Moss, D. J. H. et al. Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study. Lancet Neurol. 16, 701–711 (2017).

    Article
    CAS
    PubMed

    Google Scholar

  • Handsaker, R. E. et al. Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease. Cell 188, 623–639 (2025).

    Article
    CAS
    PubMed

    Google Scholar

  • The UK Biobank Whole-Genome Sequencing Consortium. Whole-genome sequencing of 490,640 UK Biobank participants. Nature 645, 692–701 (2025).

    Article
    CAS

    Google Scholar

  • The All of Us Research Program Genomics Investigators. Genomic data in the All of Us Research Program. Nature 627, 340–346 (2024).

    Article
    CAS

    Google Scholar

  • Tanudisastro, H. A., Deveson, I. W., Dashnow, H. & MacArthur, D. G. Sequencing and characterizing short tandem repeats in the human genome. Nat. Rev. Genet. 25, 460–475 (2024).

    Article
    CAS
    PubMed

    Google Scholar

  • Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Khristich, A. N. & Mirkin, S. M. On the wrong DNA track: molecular mechanisms of repeat-mediated genome instability. J. Biol. Chem. 295, 4134–4170 (2020).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Lundström, O. S. et al. WebSTR: a population-wide database of short tandem repeat variation in humans. J. Mol. Biol. 435, 168260 (2023).

    Article
    PubMed

    Google Scholar

  • Palamara, P. F. et al. Leveraging distant relatedness to quantify human mutation and gene-conversion rates. Am. J. Hum. Genet. 97, 775–789 (2015).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Tian, X., Browning, B. L. & Browning, S. R. Estimating the genome-wide mutation rate with three-way identity by descent. Am. J. Hum. Genet. 105, 883–893 (2019).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Tian, X., Cai, R. & Browning, S. R. Estimating the genome-wide mutation rate from thousands of unrelated individuals. Am. J. Hum. Genet. 109, 2178–2184 (2022).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Chung, M. et al. Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I. Nat. Genet. 5, 254–258 (1993).

    Article
    CAS
    PubMed

    Google Scholar

  • Eichler, E. E. et al. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat. Genet. 8, 88–94 (1994).

    Article
    CAS
    PubMed

    Google Scholar

  • Matuszek, Z. et al. Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice. Nat. Genet. 57, 1437–1451 (2025).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Shinde, D., Lai, Y., Sun, F. & Arnheim, N. Taq DNA polymerase slippage mutation rates measured by PCR and quasi-likelihood analysis: (CA/GT)n and (A/T)n microsatellites. Nucleic Acids Res. 31, 974–980 (2003).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Raz, O. et al. Short tandem repeat stutter model inferred from direct measurement of in vitro stutter noise. Nucleic Acids Res. 47, 2436–2445 (2019).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Sehgal, A., Ziaei Jam, H., Shen, A. & Gymrek, M. Genome-wide detection of somatic mosaicism at short tandem repeats. Bioinformatics 40, btae485 (2024).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Goodwin, S., McPherson, J. D. & McCombie, W. R. Coming of age: ten years of next-generation sequencing technologies. Nat. Rev. Genet. 17, 333–351 (2016).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Ashizawa, T., Dubel, J. R. & Harati, Y. Somatic instability of CTG repeat in myotonic dystrophy. Neurology 43, 2674–2674 (1993).

    Article
    CAS
    PubMed

    Google Scholar

  • Mouro Pinto, R. et al. Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1. Hum. Mol. Genet. 29, 2551–2567 (2020).

    Article
    PubMed
    PubMed Central

    Google Scholar

  • Morales, F. et al. Individual-specific levels of CTG•CAG somatic instability are shared across multiple tissues in myotonic dystrophy type 1. Hum. Mol. Genet. 32, 621–631 (2023).

    Article
    CAS
    PubMed

    Google Scholar

  • Kacher, R. et al. CAG repeat mosaicism is gene specific in spinocerebellar ataxias. Am. J. Hum. Genet. 111, 913–926 (2024).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Zarouchlioti, C. et al. Tissue-specific TCF4 triplet repeat instability revealed by optical genome mapping. EBioMedicine 108, 105328 (2024).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Laabs, B.-H. et al. Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism. Nat. Commun. 12, 3216 (2021).

    Article
    ADS
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Maza, A. M. et al. MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism. Preprint at bioRxiv https://doi.org/10.1101/2025.05.14.653432 (2025).

  • Dolzhenko, E. et al. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res. 27, 1895–1903 (2017).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Hafford-Tear, N. J. et al. CRISPR/Cas9-targeted enrichment and long-read sequencing of the Fuchs endothelial corneal dystrophy–associated TCF4 triplet repeat. Genet. Med. 21, 2092–2102 (2019).

    Article
    PubMed
    PubMed Central

    Google Scholar

  • Arab, K. et al. GADD45A binds R-loops and recruits TET1 to CpG island promoters. Nat. Genet. 51, 217–223 (2019).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Kim, K.-H. et al. Genetic and functional analyses point to FAN1 as the source of multiple Huntington disease modifier effects. Am. J. Hum. Genet. 107, 96–110 (2020).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Wieben, E. D. et al. A common trinucleotide repeat expansion within the transcription factor 4 (TCF4, E2-2) gene predicts fuchs corneal dystrophy. PLoS ONE 7, e49083 (2012).

    Article
    ADS
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Fautsch, M. P. et al. TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease. Prog. Retin. Eye Res. 81, 100883 (2021).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Gorman, B. R. et al. A multi-ancestry GWAS of Fuchs corneal dystrophy highlights the contributions of laminins, collagen, and endothelial cell regulation. Commun. Biol. 7, 418 (2024).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Verma, A. et al. Diversity and scale: genetic architecture of 2068 traits in the VA Million Veteran Program. Science 385, eadj1182 (2024).

    Article
    CAS
    PubMed

    Google Scholar

  • Palombo, F. et al. hMutSβ, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNA. Curr. Biol. 6, 1181–1184 (1996).

    Article
    CAS
    PubMed

    Google Scholar

  • Genschel, J., Littman, S. J., Drummond, J. T. & Modrich, P. Isolation of MutSβ from human cells and comparison of the mismatch repair specificities of MutSβ and MutSα. J. Biol. Chem. 273, 19895–19901 (1998).

    Article
    CAS
    PubMed

    Google Scholar

  • Hazra, T. K. et al. Identification and characterization of a novel human DNA glycosylase for repair of cytosine-derived lesions. J. Biol. Chem. 277, 30417–30420 (2002).

    Article
    CAS
    PubMed

    Google Scholar

  • Costelloe, T. et al. The yeast Fun30 and human SMARCAD1 chromatin remodellers promote DNA end resection. Nature 489, 581–584 (2012).

    Article
    ADS
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Mouro Pinto, R. et al. In vivo CRISPR–Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington’s disease. Nat. Genet. 57, 314–322 (2025).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Jadhav, B. et al. A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability. Nat. Genet. 56, 2322–2332 (2024).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Van Kuilenburg, A. B. P. et al. Glutaminase deficiency caused by short tandem repeat expansion in GLS. N. Engl. J. Med. 380, 1433–1441 (2019).

    Article
    PubMed
    PubMed Central

    Google Scholar

  • Fazal, S. et al. Repeat expansions nested within tandem CNVs: a unique structural change in GLS exemplifies the diagnostic challenges of non-coding pathogenic variation. Hum. Mol. Genet. 32, 46–54 (2023).

    Article
    CAS
    PubMed

    Google Scholar

  • Rumping, L. et al. Identification of a loss-of-function mutation in the context of glutaminase deficiency and neonatal epileptic encephalopathy. JAMA Neurol. 76, 342 (2019).

    Article
    PubMed

    Google Scholar

  • Malik, I., Kelley, C. P., Wang, E. T. & Todd, P. K. Molecular mechanisms underlying nucleotide repeat expansion disorders. Nat. Rev. Mol. Cell Biol. 22, 589–607 (2021).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Ciosi, M. et al. A genetic association study of glutamine-encoding DNA sequence structures, somatic CAG expansion, and DNA repair gene variants, with Huntington disease clinical outcomes. EBioMedicine 48, 568–580 (2019).

    Article
    CAS
    PubMed
    PubMed Central

    Google Scholar

  • Hujoel M. L. A. et al. Code and pheWAS data from ‘Insights into DNA repeat expansions among 900,000 biobank participants’. Zenodo https://doi.org/10.5281/zenodo.17419996 (2025).



  • ■ مصدر الخبر الأصلي

    نشر لأول مرة على: yalebnan.org

    تاريخ النشر: 2026-01-08 11:40:00

    الكاتب: ahmadsh

    تنويه من موقعنا

    تم جلب هذا المحتوى بشكل آلي من المصدر:
    yalebnan.org
    بتاريخ: 2026-01-08 11:40:00.
    الآراء والمعلومات الواردة في هذا المقال لا تعبر بالضرورة عن رأي موقعنا والمسؤولية الكاملة تقع على عاتق المصدر الأصلي.

    ملاحظة: قد يتم استخدام الترجمة الآلية في بعض الأحيان لتوفير هذا المحتوى.

    اظهر المزيد

    مقالات ذات صلة

    اترك تعليقاً

    لن يتم نشر عنوان بريدك الإلكتروني. الحقول الإلزامية مشار إليها بـ *

    زر الذهاب إلى الأعلى