The DOI matches its Crossref record; 155 of the 157 references it cites were found in a registry or an index.
Repeat instability: mechanisms of dynamic mutations
Abstract
Disease-causing repeat instability is an important and unique form of mutation that is linked to more than 40 neurological, neurodegenerative and neuromuscular disorders. DNA repeat expansion mutations are dynamic and ongoing within tissues and across generations. The patterns of inherited and tissue-specific instability are determined by both gene-specific cis-elements and trans-acting DNA metabolic proteins. Repeat instability probably involves the formation of unusual DNA structures during DNA replication, repair and recombination. Experimental advances towards explaining the mechanisms of repeat instability have broadened our understanding of this mutational process. They have revealed surprising ways in which metabolic pathways can drive or protect from repeat instability.
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“By a process that is poorly understood, a small number of specific normal-length STRs undergo somatic or germline expansion and transition to intermediate, pre-mutation, and mutation (affected) repeat unit tract lengths (Mirkin, 2007; Pearson et al., 2005).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Pearson et al., 2005
In the citing paper
“Notably, a large number of daSTRs known to undergo paternal instability (McMurray, 2010; Pearson et al., 2005) co-localized to boundaries in mouse sperm and not in mouse oocytes (Du et al., 2017), suggesting that daSTRs could be at boundaries when germ line expansion takes place (Figure S3).”
From Disease-Associated Short Tandem Repeats Co-localize with Chromatin Domain Boundaries (2018) · cites this paper as Pearson et al., 2005
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“CTCF has also been implicated in genetic instability, which occurs in most repeat expansion disease”
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30 years of repeat expansion disorders: What have we learned and what are the remaining challenges?
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“…formed within expanded microsatellites stall replication fork progression in vivo, and a causal link between non-B DNA structure formation, replication fork stalling, and genome instability has been demonstrated in microsatellite expansion disease etiology (Pearson et al., 2005; Mirkin, 2007).”
C9orf72 hypermethylation protects against repeat expansion-associated pathology in ALS/FTD
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“rANT aggregates have been proposed to be toxic [2, 46], perhaps through disruption of cellular pathways like autophagy or altered proteostasis [9, 50].”
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“Trinucleotide repeat expansions play a role in several neurological, neurodegenerative, and neuromuscular disorders such as Huntington’s disease, FXS, spinocerebellar ataxia, andmyotonic dystrophy (Pearson et al., 2005).”
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“…by a GAA expansion in the first intron of the frataxin (FXN) gene (Table 1; note: the repeat on the coding strand is used to refer to the disease-causing repeat for a particular locus) (reviewed in Gatchel & Zoghbi, 2005; Lopez et al., 2010; McMurray, 2010; Mirkin, 2006; Pearson et al., 2005).”
BackgroundCamnasio, S., Carri, A. D., Lombardo, A., Grad, I., Mariotti, C., Castucci, A., Rozell, B., Riso, P. L., Castiglioni, V., Zuccato, C., et al. (2012) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.12.042 · Cited by 175
MSH3 Polymorphisms and Protein Levels Affect CAG Repeat Instability in Huntington's Disease Mice
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“Repeat length, sequence of repeat, purity of the repeat, genomic context and DNA metabolizing proteins can contribute to patterns of repeat instability in mouse models of trinucleotide repeat diseases such as DM1, HD and SCA7 [19].”
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Transcription promotes contraction of CAG repeat tracts in human cells
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FAN1 modifies Huntington’s disease progression by stabilizing the expanded HTT CAG repeat
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“Longer CAG repeats are more unstable and prone to increased rates of expansion (35), a feature recapitulated in our U20S cells expressing HTT exon 1 with a series of CAG repeat lengths (Fig.”
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“Since the discovery in 1991 that the expansion of unstable trinucleotide repeats (TNR) can cause disease, multiple disorders have been shown to be associated with expanded microsatellites, mostly CNG trinucleotides (Pearson et al. 2005).”
BackgroundLópez, A., Nakamori, M., Tomé, S., Chitayat, D. A., Gourdon, G., Thornton, C. A., & Pearson, C. E. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq427 · Cited by 160
“Such a relation exists in FRAXA in which evidence suggests that the presence of DNA methylation protects against contractions of expanded CGG tracts (63,80).”
Functional Mechanisms of Microsatellite DNA in Eukaryotic Genomes
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Replication-dependent instability at (CTG)•(CAG) repeat hairpins in human cells
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“In individuals with DM1, instability of the (CTG)•(CAG) repeats at the DMPK locus is evident during germ cell development and in somatic cell”
BackgroundMechanism of a genetic glissando*: structural biology of indel mutations
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A slipped-CAG DNA-binding small molecule induces trinucleotide-repeat contractions in vivo
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“repeats (for review, see [8]).”
Gécz, J., Cloosterman, D., & Partington, M. W. (2006) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2006.04.003 · Cited by 147
“Alternatively, DNA replication- or DNA repair-based mechanisms similar to those proposed for dynamic mutations might be involved [17].”
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“transcription contribute to instability of CAG/CTG repeats, although the underlying mechanisms remain elusive [10].”
BackgroundDeterminants of R-loop formation at convergent bidirectionally transcribed trinucleotide repeats
Reddy, K., Tam, M., Bowater, R. P., Barber, M., Tomlinson, M. J., Edamura, K. N., Wang, Y., & Pearson, C. E. (2010) · Nucleic Acids Research · doi:10.1093/nar/gkq935 · Cited by 140
“Expansion of (CAG) (CTG) tracts, where the CAG strand is transcribed, is responsible for at least nine polyglutamine diseases, including Huntington’s disease, spinocerebellar ataxia types 1–3, 6, 7, 8, 17 (SCA1, etc.), and spinal bulbar muscular atrophy (SBMA) (6).”
InfluentialNolin, S. L., Glicksman, A., Ersalesi, N., Dobkin, C., Brown, W. T., Cao, R., Blatt, E. B., Sah, S., Latham, G. J., & Hadd, A. G. (2014) · Genetics in Medicine · doi:10.1038/gim.2014.106 · Cited by 144
Trinucleotide repeats in human genome and exome
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“More than 20 genetic disorders belong to this group; they are mostly neurodegenerative and neuromuscular (10,11) disorders.”
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“This tissue-specific instability, or ‘‘somatic mosaicism’’, occurs in human patients with repeat diseases, and in mouse models of repeat instability and disease [1,8,11].”
BackgroundSelf-citationLarge-Scale Expansions of Friedreich's Ataxia GAA Repeats in Yeast
Shishkin, A. A., Voineagu, I., Matera, R. M., Cherng, N., Chernet, B. T., Krasilnikova, M. M., Narayanan, V., Lobachev, K. S., & Mirkin, S. M. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.06.017 · Cited by 138
“…strand misalignment promoted by the stable secondary structures during one of those processes is believed to be central for repeat instability (reviewed in McMurray, 1999; 82 Molecular Cell 35, 82–92, July 10, 2009 ª2009 Elsevier Inc. Mirkin, 2006; Pearson et al., 2005; Wells et al., 2005).”
BackgroundDelivery and therapeutic applications of gene editing technologies ZFNs, TALENs, and CRISPR/Cas9
LaFountaine, J. S., Fathe, K., & Smyth, H. D. C. (2015) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2015.08.029 · Cited by 111
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CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease
Jung, J., & Bonini, N. M. (2007) · Science · doi:10.1126/science.1139517 · Cited by 133
Echinodermata: The Complex Immune System in Echinoderms
Smith, L. C., Arizza, V., Hudgell, M. A. B., Barone, G., Bodnar, A. G., Buckley, K. M., Cunsolo, V., Dheilly, N. M., Franchi, N., Fugmann, S. D., et al. (2018) · Springer eBooks · doi:10.1007/978-3-319-76768-0_13 · Cited by 131
“This repetitive structure may contribute to gene diversification by promoting genomic instability, as has been noted in other systems (Pearson et al. 2005; Thys et al. 2014), perhaps through SpTrf gene deletion and by blocking the progression of sequence homogenization of clustered genes from gene conversion (Miller e…”
BackgroundSopher, B. L., Ladd, P. D., Pineda, V. V., Libby, R. T., Sunkin, S. M., Hurley, J. B., Thienes, C. P., Gaasterland, T., Filippova, G. N., & Spada, A. R. L. (2011) · Neuron · doi:10.1016/j.neuron.2011.05.027 · Cited by 128
Predictive testing for Huntington disease: interpretation and significance of intermediate alleles
Semaka, A., Creighton, S., Warby, S. C., & Hayden, M. R. (2006) · Clinical Genetics · doi:10.1111/j.1399-0004.2006.00668.x · Cited by 133
“Germline repeat instability is observed in all trinucleotide disorders (22).”
BackgroundInfluentialAnalysis of somatic microsatellite indels identifies driver events in human tumors
Maruvka, Y. E., Mouw, K. W., Karlić, R., Parasuraman, P., Kamburov, A., Polak, P. P., Haradhvala, N. J., Hess, J. M., Rheinbay, E., Brody, Y., et al. (2017) · Nature Biotechnology · doi:10.1038/nbt.3966 · Cited by 126
Structural Diversity of Triplet Repeat RNAs
Sobczak, K., Michlewski, G., de Mezer, M., Kierzek, E., Krol, J., Olejniczak, M., Kierzek, R., & Krzyżosiak, W. J. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.078790 · Cited by 126
Epigenetic mechanisms and genome stability
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“, DNA hairpins), particularly during replication, transcription, and DNA repair (Pearson et al. 2005).”
BackgroundRepeat‐associated non‐AUG translation in C9orf72‐ALS/FTD is driven by neuronal excitation and stress
Westergard, T., McAvoy, K., Russell, K. A., Wen, X., Pang, Y., Verdone, B. M., Pasinelli, P., Trotti, D., & Haeusler, A. R. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201809423 · Cited by 126
“NREs have been associated with over 30 neurological and neuromuscular disorders (Pearson et al, 2005; McMurray, 2010).”
BackgroundGenome plasticity in Candida albicans is driven by long repeat sequences
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Roles of DNA Polymerases in Replication, Repair, and Recombination in Eukaryotes
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“Furthermore, the rate of expansion in somatic cells can vary within the same tissue [8].”
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“For neurons, which no longer divide, the ongoing instability of their repeats cannot depend on DNA replication, a process often suggested as the primary mechanism for germ line instability (20, 53).”
BackgroundInfluentialIntron retention induced by microsatellite expansions as a disease biomarker
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“While GC-rich trinucleotide expansions (exp) predominate in exonic regions, intron mutations are composed of 3- to 6-bp repeats that vary considerably in GC content (20–100%) (6, 8).”
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“Similar observations have been made in trinucleotide-repeat expansion disorders, where expansions in the cerebellum have been found to be shorter than in other brain regions (24).”
ResultDetection of structural variants and indels within exome data
Karakoç, E., Alkan, C., O’Roak, B. J., Dennis, M. Y., Vives, L., Mark, K. M. K., Rieder, M. J., Nickerson, D. A., & Eichler, E. E. (2011) · Nature Methods · doi:10.1038/nmeth.1810 · Cited by 118
“Such regions are subject to higher mutation rates, due in part to their greater potential for replication slippage 14 .”
The Intra-S Checkpoint Responses to DNA Damage
Iyer, D., & Rhind, N. (2017) · Genes · doi:10.3390/genes8020074 · Cited by 131
“Replication stress can also be caused be intrinsically difficult to replicate sequences in the genome, such as G-quadruplexes and repeats, which can lead to replication fork slippage and chromosomal breaks [3,4,15].”
Background
Metadata
- Authors
- Pearson, C. E., Edamura, K. N., & Cleary, J. D.
- Affiliations
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Corresponding author
- Pearson, Christopher E.
- Venue
- Nature Reviews Genetics
- Published
- 2005-10
- Volume
- 6
- Issue
- 10
- Pages
- 729-742
- ISSN
- 1471-0056 (ISSN-L)
- 1471-0064
- OpenAlex
- W2087505473
- Cited by
- 924
- References
- 157
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 45 · 2023: 29 · 2022: 25 · 2021: 54 · 2020: 27 · 2019: 38 · 2018: 53 · 2017: 45 · 2016: 58 · 2015: 41 · 2014: 55 · 2013: 46 · 2012: 56
- FWCI
- 3.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- repeat instability, dynamic mutation, trinucleotide repeat disorders, neurodegenerative diseases, neuromuscular disorders, cis-regulatory elements, trans-acting proteins, DNA replication, DNA repair, DNA recombination, DNA secondary structure
- MeSH terms
- DNA Repair, DNA Replication, Humans, Models, Genetic, Mutation, Recombination, Genetic, Trinucleotide Repeat Expansion, Heredodegenerative Disorders, Nervous System, DNA Repeat Expansion, Genomic Instability
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