Patterns of de novo tandem repeat mutations and their role in autism
Open accessAbstract
Autism spectrum disorder (ASD) is an early-onset developmental disorder characterized by deficits in communication and social interaction and restrictive or repetitive behaviours 1,2. Family studies demonstrate that ASD has a substantial genetic basis with contributions both from inherited and de novo variants 3,4. 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 family 5. 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 humans 6. TR expansions are implicated in dozens of neurological and psychiatric disorders 7. 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Emerging evidence suggests a role for other classes of genetic variants (e.g., rare inherited and de novo tandem repeats) in autism.
“yet emerging evidence suggests a role for other classes (for example, rare inherited and de novo tandem repeats) of genetic variants as well17,19,60,61.”
From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [61]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Diagnostic and Statistical Manual of Mental Disorders
American Psychiatric Association (2013) · doi:10.1176/appi.books.9780890425596 · Cited by 116,369 · see citing works
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
The Human Genome Browser at UCSC
Kent, W. J., Sugnet, C. W., Furey, T. S., Roskin, K. M., Pringle, T. H., Zahler, A. M., & Haussler, A. D. (2002) · Genome Research · doi:10.1101/gr.229102 · Cited by 10,400 · see citing works
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, Lek, M., Karczewski, K. J., Minikel, E. V., Samocha, K. E., Banks, E., Fennell, T., O’Donnell-Luria, A. H., Ware, J. S., Hill, A. J., et al. (2016) · Nature · doi:10.1038/nature19057 · Cited by 9,587 · see citing works
The mutational constraint spectrum quantified from variation in 141,456 humans
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., et al. (2020) · Nature · doi:10.1038/s41586-020-2308-7 · Cited by 9,434 · see citing works
Genetic effects on gene expression across human tissues
GTEx Consortium (2017) · Nature · doi:10.1038/nature24277 · Cited by 4,036 · see citing works
Buniello, A., MacArthur, J. A. L., Cerezo, M., Harris, L. W., Hayhurst, J., Malangone, C., McMahon, A., Morales, J., Mountjoy, E., Sollis, E., et al. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1120 · Cited by 4,000 · see citing works
An economic method for the fluorescent labeling of PCR fragments
Schuelke, M. (2000) · Nature Biotechnology · doi:10.1038/72708 · Cited by 3,616 · see citing works
CADD: predicting the deleteriousness of variants throughout the human genome
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J., & Kircher, M. (2019) · Nucleic Acids Research · doi:10.1093/nar/gky1016 · Cited by 3,534 · see citing works
The contribution of de novo coding mutations to autism spectrum disorder
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., et al. (2014) · Nature · doi:10.1038/nature13908 · Cited by 2,585 · see citing works
ChromHMM: automating chromatin-state discovery and characterization
Ernst, J., & Kellis, M. (2012) · Nature Methods · doi:10.1038/nmeth.1906 · Cited by 2,489 · see citing works
BEDTools: The Swiss‐Army Tool for Genome Feature Analysis
Quinlan, A. R. (2014) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1112s47 · Cited by 2,286 · see citing works
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165 · see citing works
Identifying a High Fraction of the Human Genome to be under Selective Constraint Using GERP++
Davydov, E. V., Goode, D. L., Sirota, M., Cooper, G. M., Sidow, A., & Batzoglou, S. (2010) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1001025 · Cited by 1,757 · see citing works
The mutational constraint spectrum quantified from variation in 141,456 humans
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., et al. (2019) · doi:10.1101/531210 · Cited by 1,662 · see citing works
Mutation of human short tandem repeats
Weber, J. L., & Wong, C. (1993) · Human Molecular Genetics · doi:10.1093/hmg/2.8.1123 · Cited by 1,574 · see citing works
ART: a next-generation sequencing read simulator
Huang, W., Li, L., Myers, J. R., & Marth, G. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr708 · Cited by 1,548 · see citing works
Transcriptional landscape of the prenatal human brain
Miller, J. A., Ding, S.-L., Sunkin, S. M., Smith, K. A., Ng, L., Szafer, A., Ebbert, A., Riley, Z. L., Royall, J. J., Aiona, K., et al. (2014) · Nature · doi:10.1038/nature13185 · Cited by 1,325 · see citing works
Most genetic risk for autism resides with common variation
Gaugler, T., Klei, L., Sanders, S. J., Bodea, C. A., Goldberg, A. P., Lee, A. B., Mahajan, M., Manaa, D., Pawitan, Y., Reichert, J., et al. (2014) · Nature Genetics · doi:10.1038/ng.3039 · Cited by 1,239 · see citing works
A framework for the interpretation of de novo mutation in human disease
Samocha, K. E., Robinson, E. B., Sanders, S. J., Stevens, C., Sabo, A., McGrath, L. M., Kosmicki, J. A., Rehnström, K., Mallick, S., Kirby, A., et al. (2014) · Nature Genetics · doi:10.1038/ng.3050 · Cited by 979 · see citing works
The Simons Simplex Collection: a resource for identification of autism genetic risk factors
Fischbach, G. D., & Lord, C. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.006 · Cited by 725 · see citing works
Timing, rates and spectra of human germline mutation
Rahbari, R., Wüster, A., Lindsay, S., Hardwick, R. J., Alexandrov, L. B., Turki, S. H. A., Dominiczak, A. F., Morris, A. D., Porteous, D. J., Smith, B. H., et al. (2015) · Nature Genetics · doi:10.1038/ng.3469 · Cited by 632 · see citing works
Whole-Genome Sequencing in Autism Identifies Hot Spots for De Novo Germline Mutation
Michaelson, J. J., Shi, Y., Gujral, M., Zheng, H., Malhotra, D., Jin, X., Jian, M., Liu, G., Greer, D., Bhandari, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.11.019 · Cited by 544 · see citing works
Tandem repeats mediating genetic plasticity in health and disease
Hannan, A. J. (2018) · Nature Reviews Genetics · doi:10.1038/nrg.2017.115 · Cited by 446 · see citing works
Heterogeneous mutation processes in human microsatellite DNA sequences
Ellegren, H. (2000) · Nature Genetics · doi:10.1038/74249 · Cited by 377 · see citing works
A direct characterization of human mutation based on microsatellites
Sun, J. X., Helgason, A., Másson, G., Ebenesersdóttir, S. S., Li, H., Mallick, S., Gnerre, S., Patterson, N. J., Kong, A., Reich, D., et al. (2012) · Nature Genetics · doi:10.1038/ng.2398 · Cited by 342 · see citing works
Genomic Patterns of De Novo Mutation in Simplex Autism
Turner, T. N., Coe, B. P., Dickel, D. E., Hoekzema, K., Nelson, B. J., Zody, M. C., Kronenberg, Z. N., Hormozdiari, F., Raja, A. N., Pennacchio, L. A., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.047 · Cited by 330 · see citing works
Genome-wide profiling of heritable and de novo STR variations
Willems, T., Zielinski, D., Yuan, J., Gordon, A., Gymrek, M., & Erlich, Y. (2017) · Nature Methods · doi:10.1038/nmeth.4267 · Cited by 329 · see citing works
Genome-wide de novo risk score implicates promoter variation in autism spectrum disorder
An, J.-Y., Lin, K., Zhu, L., Werling, D. M., Dong, S., Brand, H., Wang, H. Z., Zhao, X., Schwartz, G. B., Collins, R. L., et al. (2018) · Science · doi:10.1126/science.aat6576 · Cited by 316 · see citing works
Werling, D. M., Brand, H., An, J.-Y., Stone, M. R., Zhu, L., Glessner, J. T., Collins, R. L., Dong, S., Layer, R. M., Markenscoff-Papadimitriou, E., et al. (2018) · Nature Genetics · doi:10.1038/s41588-018-0107-y · Cited by 293 · see citing works
Whole-genome deep-learning analysis identifies contribution of noncoding mutations to autism risk
Zhou, J., Park, C. Y., Theesfeld, C. L., Wong, A. K., Yuan, Y., Scheckel, C., Fak, J. J., Funk, J., Yao, K., Tajima, Y., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0420-0 · Cited by 287 · see citing works
The impact of short tandem repeat variation on gene expression
Feupe, S. F., Margoliash, J., Wang, C., Saini, S., Yanicky, R., Shleizer-Burko, S., Goren, A., & Gymrek, M. (2019) · Nature Genetics · doi:10.1038/s41588-019-0521-9 · Cited by 271 · see citing works
Self-citationProfiling the genome-wide landscape of tandem repeat expansions
(2019) · doi:10.1093/nar/gkz501 · Cited by 270 · see citing works
Getting to the cores of autism
Iakoucheva, L. M., Muotri, A. R., & Sebat, J. (2019) · Cell · doi:10.1016/j.cell.2019.07.037 · Cited by 260 · see citing works
Genome-wide detection of tandem DNA repeats that are expanded in autism
Trost, B., Engchuan, W., Nguyen, C. M., Thiruvahindrapuram, B., Dolzhenko, E., Backstrom, I., Mirceta, M., Mojarad, B. A., Yin, Y., Dov, A., et al. (2020) · Nature · doi:10.1038/s41586-020-2579-z · Cited by 238 · see citing works
Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite
Grünewald, T. G. P., Bernard, V., Gilardi‐Hebenstreit, P., Raynal, V., Surdez, D., Aynaud, M.-M., Mirabeau, O., Cidre‐Aranaz, F., Tirode, F., Zaïdi, S., et al. (2015) · Nature Genetics · doi:10.1038/ng.3363 · Cited by 189 · see citing works
Mutation Patterns at Dinucleotide Microsatellite Loci in Humans
Huang, Q.-Y., Xu, F., Shen, H., et al. (2002) · The American Journal of Human Genetics · doi:10.1086/338997 · Cited by 173 · see citing works
Krebs, M., Betancur, C., Leroy, S., Bourdel, M., Gillberg, C., & Leboyer, M. (2002) · Molecular Psychiatry · doi:10.1038/sj.mp.4001071 · Cited by 107 · see citing works
Autism risk in offspring can be assessed through quantification of male sperm mosaicism
Breuss, M. W., Antaki, D., George, R. D., Kleiber, M. L., James, K. N., Ball, L., Hong, O., Mitra, I., Yang, X., Wirth, S. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0711-0 · Cited by 105 · see citing works
Self-citationA Genomic Portrait of Human Microsatellite Variation
Payseur, B. A., Jing, P., & Haasl, R. J. (2010) · Molecular Biology and Evolution · doi:10.1093/molbev/msq198 · Cited by 103 · see citing works
Population-Scale Sequencing Data Enable Precise Estimates of Y-STR Mutation Rates
Willems, T., Gymrek, M., Poznik, G. D., Tyler‐Smith, C., The 1000 Genomes Project Chromosome Y Group, & Erlich, Y. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.04.001 · Cited by 97 · see citing works
Self-citationInterpreting short tandem repeat variations in humans using mutational constraint
Gymrek, M., Willems, T., Reich, D., & Erlich, Y. (2017) · Nature Genetics · doi:10.1038/ng.3952 · Cited by 94 · see citing works
Self-citationThe genetic landscape of autism spectrum disorders
Rosti, R. Ö., Sadek, A. A., Vaux, K. K., & Gleeson, J. G. (2013) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.12278 · Cited by 89 · see citing works
Microsatellites as Targets of Natural Selection
Haasl, R. J., & Payseur, B. A. (2012) · Molecular Biology and Evolution · doi:10.1093/molbev/mss247 · Cited by 74 · see citing works
TRTools: a toolkit for genome-wide analysis of tandem repeats
Mousavi, N., Margoliash, J., Pusarla, N., Saini, S., Yanicky, R., & Gymrek, M. (2020) · Bioinformatics · doi:10.1093/bioinformatics/btaa736 · Cited by 65 · see citing works
Self-citationSimultaneous Estimation of All the Parameters of a Stepwise Mutation Model
Fu, Y., & Chakraborty, R. (1998) · Genetics · doi:10.1093/genetics/150.1.487 · Cited by 39 · see citing works
Inter-allelic interactions play a major role in microsatellite evolution
Amos, W., Kosanović, D., & Eriksson, A. (2015) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2015.2125 · Cited by 17 · see citing works
TRTools: a toolkit for genome-wide analysis of tandem repeatsPreprint
Mousavi, N., Margoliash, J., Pusarla, N., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.17.996033 · Cited by 11 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [35]Li H Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv: Genomics (2013).
Cited by
Sorted by citations
Molecular mechanisms underlying nucleotide repeat expansion disorders
Malik, I., Kelley, C. P., Wang, E. T., & Todd, P. K. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00382-6 · Cited by 363 · see citing works
Antaki, D., Guevara, J., Maihofer, A. X., Klein, M., Gujral, M., Grove, J., Carey, C. E., Hong, O., Arranz, M. J., Hervas, A., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01064-5 · Cited by 206 · see citing works
Genetic correlates of phenotypic heterogeneity in autism
Warrier, V., Zhang, X., Reed, P., Havdahl, A., Moore, T. M., Cliquet, F., Leblond, C. S., Rolland, T., Rosengren, A., LEAP, E.-A., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01072-5 · Cited by 152 · see citing works
Single-cell genomics meets human genetics
Cuomo, A. S. E., Nathan, A., Raychaudhuri, S., MacArthur, D. G., & Powell, J. E. (2023) · Nature Reviews Genetics · doi:10.1038/s41576-023-00599-5 · Cited by 124 · see citing works
Wendt, F. R., Pathak, G. A., & Polimanti, R. (2022) · Nature Communications · doi:10.1038/s41467-022-35423-x · Cited by 12 · see citing works
- Authors
- Mitra, I., Huang, B., Mousavi, N., Ma, N., Lamkin, M., Yanicky, R., Shleizer-Burko, S., Lohmueller, K. E., & Gymrek, M.
- Affiliations
- University of California San Diego (US)
- University of California, Los Angeles (US)
- Corresponding author
- Lohmueller, Kirk E.
- Gymrek, Melissa
- ORCID
- Venue
- Nature
- Published
- 2021-01-13
- Volume
- 589
- Issue
- 7841
- Pages
- 246-250
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7810352
- OpenAlex
- W3119240720
- Cited by
- 194
- References
- 48
- Citations by year
- 2026: 24 · 2025: 40 · 2024: 33 · 2023: 39 · 2022: 37 · 2021: 19 · 2020: 1 · 2012: 1
- FWCI
- 17.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5r21hg010070-02, DP5OD024577)
- National Human Genome Research Institute (R21 HG010070, R01HG010149)
- National Institute of General Medical Sciences (T32GM008806, R35GM119856)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, de novo mutations, copy number alterations, repeat expansion, unaffected siblings
- MeSH terms
- Autism Spectrum Disorder, Adolescent, Adult, Brain, Child, Female, Fetus, Humans, Male, Middle Aged, Paternal Age, Least-Squares Analysis, Germ-Line Mutation, Genetic Predisposition to Disease, DNA Repeat Expansion, Young Adult, DNA Copy Number Variations
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
