Comprehensive identification of tandem repeats associated with splicing in humans

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K15646
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Kyoto University (2023); Yokohama City University (2022)
• Principal Investigator: HAMANAKA Kohei 京都大学, 高等研究院, 特定助教 (20801129)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: タンデムリピート / スプライシング / リピート伸長病

Outline of Final Research Achievements

Tandem repeats (TRs) are one of the largest sources of polymorphism, and their length is associated with gene regulation. Although previous studies reported several tandem repeats regulating gene splicing in cis (spl-TRs), no large-scale study has been conducted. In this study, we established a genome-wide catalog of 9537 spl-TRs with a total of 58,290 significant TR-splicing associations across 49 tissues (false discovery rate 5%) by using Genotype-Tissue Expression (GTEx) Project data. Regression models explaining splicing variation by using spl-TRs and other flanking variants suggest that at least some of the spl-TRs directly modulate splicing. In our catalog, two spl-TRs are known loci for repeat expansion diseases, spinocerebellar ataxia 6 (SCA6) and 12 (SCA12). Splicing alterations by these spl-TRs were compatible with those observed in SCA6 and SCA12. Thus, our comprehensive spl-TR catalog may help elucidate the pathomechanism of genetic diseases.

Free Research Field

疾患遺伝学

Academic Significance and Societal Importance of the Research Achievements

本研究で作成した、スプライシングと関連するリピートの網羅的なカタログは、将来的に希少な神経疾患のメカニズムの理解に役立つと思われる。また、遺伝性がある頻度の高い疾患（自己免疫疾患など）のメカニズムの理解にも役立つ可能性が考えられる。