Jiuyong Xie, Samuel Ogunsola, Jian Yang, Roby Joehanes, Daniel Levy, Chunyu Liu
{"title":"Genetic Variation Disrupts RNA Structural Repression of Cryptic Splice Sites.","authors":"Jiuyong Xie, Samuel Ogunsola, Jian Yang, Roby Joehanes, Daniel Levy, Chunyu Liu","doi":"10.21203/rs.3.rs-11246309/v1","DOIUrl":null,"url":null,"abstract":"<p><p>Interpreting how genetic variants alter RNA processing remains a major challenge in human genetics. Using Framingham Heart Study data and genome-wide and mutational analyses, we show that G-tract-disrupting variants activate cryptic 3' splice sites in association with predicted local RNA structural destabilization, while compensatory mutations restoring structural stability re-establish splicing repression. Approximately 1.6 million such sites occur genome-wide, revealing RNA structural disruption as a candidate mechanism of variant-induced cryptic splicing.</p>","PeriodicalId":519972,"journal":{"name":"Research square","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13692680/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Research square","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.21203/rs.3.rs-11246309/v1","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Interpreting how genetic variants alter RNA processing remains a major challenge in human genetics. Using Framingham Heart Study data and genome-wide and mutational analyses, we show that G-tract-disrupting variants activate cryptic 3' splice sites in association with predicted local RNA structural destabilization, while compensatory mutations restoring structural stability re-establish splicing repression. Approximately 1.6 million such sites occur genome-wide, revealing RNA structural disruption as a candidate mechanism of variant-induced cryptic splicing.
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