Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers
Abstract Although rare non-coding variants (RVs) play crucial roles in complex traits and diseases, understanding their mechanisms and identifying disease-associated RVs continue to be major challenges. Here we constructed a comprehensive atlas of alternative polyadenylation (APA) outliers (aOutlier...
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| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55407-3 |
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| _version_ | 1832594528271335424 |
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| author | Xudong Zou Zhaozhao Zhao Yu Chen Kewei Xiong Zeyang Wang Shuxin Chen Hui Chen Gong-Hong Wei Shuhua Xu Wei Li Ting Ni Lei Li |
| author_facet | Xudong Zou Zhaozhao Zhao Yu Chen Kewei Xiong Zeyang Wang Shuxin Chen Hui Chen Gong-Hong Wei Shuhua Xu Wei Li Ting Ni Lei Li |
| author_sort | Xudong Zou |
| collection | DOAJ |
| description | Abstract Although rare non-coding variants (RVs) play crucial roles in complex traits and diseases, understanding their mechanisms and identifying disease-associated RVs continue to be major challenges. Here we constructed a comprehensive atlas of alternative polyadenylation (APA) outliers (aOutliers), including 1334 3′ UTR and 200 intronic aOutliers, from 15,201 samples across 49 human tissues. These aOutliers exhibit unique characteristics from transcription or splicing outliers, with a pronounced RV enrichment. Mechanistically, aOutlier-RVs alter poly(A) signals and splicing sites, and perturbation indeed triggers APA events. Furthermore, we developed a Bayesian-based APA RV prediction model, which successfully pinpointed a specific set of 1799 RVs impacting 278 genes with significantly large disease effect sizes. Notably, we observed a convergence effect between rare and common cancer variants, exemplified by regulation in the DDX18 gene. Together, this study introduced an APA-enhanced framework for genome annotation, underscoring APA’s role in uncovering functional RVs linked to complex traits and diseases. |
| format | Article |
| id | doaj-art-0ca1d32970ed46c1a27a571feaeb5a67 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-0ca1d32970ed46c1a27a571feaeb5a672025-01-19T12:30:26ZengNature PortfolioNature Communications2041-17232025-01-0116111710.1038/s41467-024-55407-3Impact of rare non-coding variants on human diseases through alternative polyadenylation outliersXudong Zou0Zhaozhao Zhao1Yu Chen2Kewei Xiong3Zeyang Wang4Shuxin Chen5Hui Chen6Gong-Hong Wei7Shuhua Xu8Wei Li9Ting Ni10Lei Li11Institute of Systems and Physical Biology, Shenzhen Bay LaboratoryState Key Laboratory of Genetic Engineering, Human Phenome Institute, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityState Key Laboratory of Genetic Engineering, Human Phenome Institute, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityInstitute of Systems and Physical Biology, Shenzhen Bay LaboratoryInstitute of Systems and Physical Biology, Shenzhen Bay LaboratoryInstitute of Systems and Physical Biology, Shenzhen Bay LaboratoryInstitute of Systems and Physical Biology, Shenzhen Bay LaboratoryFudan University Shanghai Cancer Center & MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan UniversityState Key Laboratory of Genetic Engineering, Human Phenome Institute, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityDivision of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California, IrvineState Key Laboratory of Genetic Engineering, Human Phenome Institute, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan UniversityInstitute of Systems and Physical Biology, Shenzhen Bay LaboratoryAbstract Although rare non-coding variants (RVs) play crucial roles in complex traits and diseases, understanding their mechanisms and identifying disease-associated RVs continue to be major challenges. Here we constructed a comprehensive atlas of alternative polyadenylation (APA) outliers (aOutliers), including 1334 3′ UTR and 200 intronic aOutliers, from 15,201 samples across 49 human tissues. These aOutliers exhibit unique characteristics from transcription or splicing outliers, with a pronounced RV enrichment. Mechanistically, aOutlier-RVs alter poly(A) signals and splicing sites, and perturbation indeed triggers APA events. Furthermore, we developed a Bayesian-based APA RV prediction model, which successfully pinpointed a specific set of 1799 RVs impacting 278 genes with significantly large disease effect sizes. Notably, we observed a convergence effect between rare and common cancer variants, exemplified by regulation in the DDX18 gene. Together, this study introduced an APA-enhanced framework for genome annotation, underscoring APA’s role in uncovering functional RVs linked to complex traits and diseases.https://doi.org/10.1038/s41467-024-55407-3 |
| spellingShingle | Xudong Zou Zhaozhao Zhao Yu Chen Kewei Xiong Zeyang Wang Shuxin Chen Hui Chen Gong-Hong Wei Shuhua Xu Wei Li Ting Ni Lei Li Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers Nature Communications |
| title | Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers |
| title_full | Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers |
| title_fullStr | Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers |
| title_full_unstemmed | Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers |
| title_short | Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers |
| title_sort | impact of rare non coding variants on human diseases through alternative polyadenylation outliers |
| url | https://doi.org/10.1038/s41467-024-55407-3 |
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