{"title":"Interruptions impact clinical features of repeat expansion diseases, but how are they gained and lost?","authors":"Alys N Aston, Vincent Dion","doi":"10.1016/j.tig.2025.07.005","DOIUrl":null,"url":null,"abstract":"<p><p>Interruptions within expanded tandem repeats reduce somatic expansion and alter the severity of the resulting diseases. Consequently, much has been done to identify interruptions in the human population and assess their clinical impact. However, how interruptions are gained and lost is unknown. Here, we propose that synthesis-dependent microhomology-mediated end joining (SD-MMEJ) can account for most, if not all, the dynamic changes in interruptions within expanded repeats. SD-MMEJ explains the locus specificity of interruptions, why they appear near the 5' and 3' ends of expanded tracts, and how complex alleles arise within a single generation. Understanding interruption dynamics is fundamental to repeat expansion disease aetiology and therapeutic development.</p>","PeriodicalId":54413,"journal":{"name":"Trends in Genetics","volume":" ","pages":""},"PeriodicalIF":16.3000,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Trends in Genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.tig.2025.07.005","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Interruptions within expanded tandem repeats reduce somatic expansion and alter the severity of the resulting diseases. Consequently, much has been done to identify interruptions in the human population and assess their clinical impact. However, how interruptions are gained and lost is unknown. Here, we propose that synthesis-dependent microhomology-mediated end joining (SD-MMEJ) can account for most, if not all, the dynamic changes in interruptions within expanded repeats. SD-MMEJ explains the locus specificity of interruptions, why they appear near the 5' and 3' ends of expanded tracts, and how complex alleles arise within a single generation. Understanding interruption dynamics is fundamental to repeat expansion disease aetiology and therapeutic development.
期刊介绍：
Launched in 1985, Trends in Genetics swiftly established itself as a "must-read" for geneticists, offering concise, accessible articles covering a spectrum of topics from developmental biology to evolution. This reputation endures, making TiG a cherished resource in the genetic research community. While evolving with the field, the journal now embraces new areas like genomics, epigenetics, and computational genetics, alongside its continued coverage of traditional subjects such as transcriptional regulation, population genetics, and chromosome biology.
Despite expanding its scope, the core objective of TiG remains steadfast: to furnish researchers and students with high-quality, innovative reviews, commentaries, and discussions, fostering an appreciation for advances in genetic research. Each issue of TiG presents lively and up-to-date Reviews and Opinions, alongside shorter articles like Science & Society and Spotlight pieces. Invited from leading researchers, Reviews objectively chronicle recent developments, Opinions provide a forum for debate and hypothesis, and shorter articles explore the intersection of genetics with science and policy, as well as emerging ideas in the field. All articles undergo rigorous peer-review.
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