IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58970-5.html
   My bibliography  Save this article

Functional impact of splicing variants in the elaboration of complex traits in cattle

Author

Listed:
  • Mathieu Charles

    (GABI
    SIGENAE)

  • Nicolas Gaiani

    (GABI)

  • Marie-Pierre Sanchez

    (GABI)

  • Mekki Boussaha

    (GABI)

  • Chris Hozé

    (GABI
    ELIANCE)

  • Didier Boichard

    (GABI)

  • Dominique Rocha

    (GABI)

  • Arnaud Boulling

    (GABI)

Abstract

GWAS conducted directly on imputed whole genome sequence have led to the identification of numerous genetic variants associated with agronomic traits in cattle. However, such variants are often simply markers in linkage disequilibrium with the actual causal variants, which is a limiting factor for the development of accurate genomic predictions. It is possible to identify causal variants by integrating information on how variants impact gene expression into GWAS output. RNA splicing plays a major role in regulating gene expression. Thus, assessing the effect of variants on RNA splicing may explain their function. Here, we use a high-throughput strategy to functionally analyse putative splice-disrupting variants in the bovine genome. Using GWAS, massively parallel reporter assay and deep learning algorithms designed to predict splice-disrupting variants, we identify 38 splice-disrupting variants associated with complex traits in cattle, three of which could be classified as causal. Our results indicate that splice-disrupting variants are widely found in the quantitative trait loci related to these phenotypes. Using our combined approach, we also assess the validity of splicing predictors originally developed to analyse human variants in the context of the bovine genome.

Suggested Citation

  • Mathieu Charles & Nicolas Gaiani & Marie-Pierre Sanchez & Mekki Boussaha & Chris Hozé & Didier Boichard & Dominique Rocha & Arnaud Boulling, 2025. "Functional impact of splicing variants in the elaboration of complex traits in cattle," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58970-5
    DOI: 10.1038/s41467-025-58970-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58970-5
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-58970-5?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Yao-Cheng Lin & Morgane Boone & Leander Meuris & Irma Lemmens & Nadine Van Roy & Arne Soete & Joke Reumers & Matthieu Moisse & Stéphane Plaisance & Radoje Drmanac & Jason Chen & Frank Speleman & Dieth, 2014. "Genome dynamics of the human embryonic kidney 293 lineage in response to cell biology manipulations," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    2. Xena Marie Mapel & Naveen Kumar Kadri & Alexander S. Leonard & Qiongyu He & Audald Lloret-Villas & Meenu Bhati & Maya Hiltpold & Hubert Pausch, 2024. "Author Correction: Molecular quantitative trait loci in reproductive tissues impact male fertility in cattle," Nature Communications, Nature, vol. 15(1), pages 1-1, December.
    3. Eric T. Wang & Rickard Sandberg & Shujun Luo & Irina Khrebtukova & Lu Zhang & Christine Mayr & Stephen F. Kingsmore & Gary P. Schroth & Christopher B. Burge, 2008. "Alternative isoform regulation in human tissue transcriptomes," Nature, Nature, vol. 456(7221), pages 470-476, November.
    4. Laura Braccini & Elisa Ciraolo & Carlo C. Campa & Alessia Perino & Dario L. Longo & Gianpaolo Tibolla & Marco Pregnolato & Yanyan Cao & Beatrice Tassone & Federico Damilano & Muriel Laffargue & Enzo C, 2015. "PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    5. Xena Marie Mapel & Naveen Kumar Kadri & Alexander S. Leonard & Qiongyu He & Audald Lloret-Villas & Meenu Bhati & Maya Hiltpold & Hubert Pausch, 2024. "Molecular quantitative trait loci in reproductive tissues impact male fertility in cattle," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Gustavo Glusman & Juan Caballero & Max Robinson & Burak Kutlu & Leroy Hood, 2013. "Optimal Scaling of Digital Transcriptomes," PLOS ONE, Public Library of Science, vol. 8(11), pages 1-12, November.
    2. Xiaohong Li & Guy N Brock & Eric C Rouchka & Nigel G F Cooper & Dongfeng Wu & Timothy E O’Toole & Ryan S Gill & Abdallah M Eteleeb & Liz O’Brien & Shesh N Rai, 2017. "A comparison of per sample global scaling and per gene normalization methods for differential expression analysis of RNA-seq data," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-22, May.
    3. Jun Inamo & Akari Suzuki & Mahoko Takahashi Ueda & Kensuke Yamaguchi & Hiroshi Nishida & Katsuya Suzuki & Yuko Kaneko & Tsutomu Takeuchi & Hiroaki Hatano & Kazuyoshi Ishigaki & Yasushi Ishihama & Kazu, 2024. "Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Areum Han & Peter Stoilov & Anthony J Linares & Yu Zhou & Xiang-Dong Fu & Douglas L Black, 2014. "De Novo Prediction of PTBP1 Binding and Splicing Targets Reveals Unexpected Features of Its RNA Recognition and Function," PLOS Computational Biology, Public Library of Science, vol. 10(1), pages 1-18, January.
    5. Judith A Potashkin & Jose A Santiago & Bernard M Ravina & Arthur Watts & Alexey A Leontovich, 2012. "Biosignatures for Parkinson’s Disease and Atypical Parkinsonian Disorders Patients," PLOS ONE, Public Library of Science, vol. 7(8), pages 1-13, August.
    6. Wei Hu & Yangjun Wu & Qili Shi & Jingni Wu & Deping Kong & Xiaohua Wu & Xianghuo He & Teng Liu & Shengli Li, 2022. "Systematic characterization of cancer transcriptome at transcript resolution," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Jianfei Hu & Eli Boritz & William Wylie & Daniel C Douek, 2017. "Stochastic principles governing alternative splicing of RNA," PLOS Computational Biology, Public Library of Science, vol. 13(9), pages 1-20, September.
    8. Hillary M. Heiling & Douglas R. Wilson & Naim U. Rashid & Wei Sun & Joseph G. Ibrahim, 2023. "Estimating cell type composition using isoform expression one gene at a time," Biometrics, The International Biometric Society, vol. 79(2), pages 854-865, June.
    9. Zsolt Bodai & Alena L. Bishop & Valentino M. Gantz & Alexis C. Komor, 2022. "Targeting double-strand break indel byproducts with secondary guide RNAs improves Cas9 HDR-mediated genome editing efficiencies," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    10. Seungjae Lee & Yen-Chung Chen & Austin E. Gillen & J. Matthew Taliaferro & Bart Deplancke & Hongjie Li & Eric C. Lai, 2022. "Diverse cell-specific patterns of alternative polyadenylation in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    11. Wei Sun & Yufeng Liu & James J. Crowley & Ting-Huei Chen & Hua Zhou & Haitao Chu & Shunping Huang & Pei-Fen Kuan & Yuan Li & Darla Miller & Ginger Shaw & Yichao Wu & Vasyl Zhabotynsky & Leonard McMill, 2015. "IsoDOT Detects Differential RNA-Isoform Expression/Usage With Respect to a Categorical or Continuous Covariate With High Sensitivity and Specificity," Journal of the American Statistical Association, Taylor & Francis Journals, vol. 110(511), pages 975-986, September.
    12. Justin Bo-Kai Hsu & Neil Arvin Bretaña & Tzong-Yi Lee & Hsien-Da Huang, 2011. "Incorporating Evolutionary Information and Functional Domains for Identifying RNA Splicing Factors in Humans," PLOS ONE, Public Library of Science, vol. 6(11), pages 1-11, November.
    13. Stacey D Wagner & Adam J Struck & Riti Gupta & Dylan R Farnsworth & Amy E Mahady & Katy Eichinger & Charles A Thornton & Eric T Wang & J Andrew Berglund, 2016. "Dose-Dependent Regulation of Alternative Splicing by MBNL Proteins Reveals Biomarkers for Myotonic Dystrophy," PLOS Genetics, Public Library of Science, vol. 12(9), pages 1-24, September.
    14. Christopher G Bell & Sarah Finer & Cecilia M Lindgren & Gareth A Wilson & Vardhman K Rakyan & Andrew E Teschendorff & Pelin Akan & Elia Stupka & Thomas A Down & Inga Prokopenko & Ian M Morison & Jonat, 2010. "Integrated Genetic and Epigenetic Analysis Identifies Haplotype-Specific Methylation in the FTO Type 2 Diabetes and Obesity Susceptibility Locus," PLOS ONE, Public Library of Science, vol. 5(11), pages 1-12, November.
    15. Huihui Liu & Hongchao Liu & Longhao Wang & Lei Song & Guixian Jiang & Qing Lu & Tao Yang & Hu Peng & Ruijie Cai & Xingle Zhao & Ting Zhao & Hao Wu, 2023. "Cochlear transcript diversity and its role in auditory functions implied by an otoferlin short isoform," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    16. Saikat Bhattacharya & Suman Wang & Divya Reddy & Siyuan Shen & Ying Zhang & Ning Zhang & Hua Li & Michael P. Washburn & Laurence Florens & Yunyu Shi & Jerry L. Workman & Fudong Li, 2021. "Structural basis of the interaction between SETD2 methyltransferase and hnRNP L paralogs for governing co-transcriptional splicing," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    17. Yaqi Su & Zhejian Yu & Siqian Jin & Zhipeng Ai & Ruihong Yuan & Xinyi Chen & Ziwei Xue & Yixin Guo & Di Chen & Hongqing Liang & Zuozhu Liu & Wanlu Liu, 2024. "Comprehensive assessment of mRNA isoform detection methods for long-read sequencing data," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    18. Amanda R. Krysler & Christopher R. Cromwell & Tommy Tu & Juan Jovel & Basil P. Hubbard, 2022. "Guide RNAs containing universal bases enable Cas9/Cas12a recognition of polymorphic sequences," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    19. Eun-Young Lee & Su-Man Kim & Jung Hwan Hwang & Song Yee Jang & Shinhye Park & Sanghyeon Choi & Ga Seul Lee & Jungwon Hwang & Jeong Hee Moon & Paul L. Fox & Sunghoon Kim & Chul-Ho Lee & Myung Hee Kim, 2022. "Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    20. repec:plo:pone00:0169594 is not listed on IDEAS
    21. Zhiping Zhang & Bongmin Bae & Winston H. Cuddleston & Pedro Miura, 2023. "Coordination of alternative splicing and alternative polyadenylation revealed by targeted long read sequencing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58970-5. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.