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Genome variants associated with RNA splicing variation in bovine are extensively shared between tissues

Ruidong Xiang, Ben J. Hayes, Christy J. Vander Jagt, Iona M. MacLeod, Majid Khansefid, Phil J. Bowman, Zehu Yuan, Claire P. Prowse-Wilkins, Coralie M. Reich, Brett A. Mason, Josie B. Garner, Leah C. Marett, Yizhou Chen, Sunduimijid Bolormaa, Hans D. Daetwyler, Amanda J. Chamberlain, Michael E. Goddard
doi: https://doi.org/10.1101/220251
Ruidong Xiang
Faculty of Veterinary & Agricultural Science, University of Melbourne, Parkville, VIC 3010, Australia.Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Ben J. Hayes
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.Queensland Alliance for Agriculture and Food Innovation, Centre for Animal Science, University of Queensland, St. Lucia, QLD 4067, Australia.
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Christy J. Vander Jagt
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Iona M. MacLeod
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Majid Khansefid
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Phil J. Bowman
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.School of Applied Systems Biology, La Trobe University, Bundoora, VIC 3083, Australia.
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Zehu Yuan
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Claire P. Prowse-Wilkins
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Coralie M. Reich
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Brett A. Mason
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Josie B. Garner
Agriculture Victoria, Dairy Production Science, Ellinbank, VIC, 3821, Australia.
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Leah C. Marett
Agriculture Victoria, Dairy Production Science, Ellinbank, VIC, 3821, Australia.
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Yizhou Chen
Elizabeth Macarthur Agricultural Institute, New South Wales Department of Primary Industries, Camden, NSW 2570, Australia.
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Sunduimijid Bolormaa
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Hans D. Daetwyler
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.School of Applied Systems Biology, La Trobe University, Bundoora, VIC 3083, Australia.
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Amanda J. Chamberlain
Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Michael E. Goddard
Faculty of Veterinary & Agricultural Science, University of Melbourne, Parkville, VIC 3010, Australia.Agriculture Victoria, AgriBio, Centre for AgriBioscience, Bundoora, VIC 3083, Australia.
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Abstract

Background Mammalian phenotypes are shaped by numerous genome variants, many of which may regulate gene transcription or RNA splicing. To identify variants with regulatory functions in cattle, an important economic and model species, we used sequence variants to map a type of expression quantitative trait loci (expression QTLs) that are associated with variations in the RNA splicing, i.e., sQTLs. To further the understanding of regulatory variants, sQTLs were compare with other two types of expression QTLs, 1) variants associated with variations in gene expression, i.e., geQTLs and 2) variants associated with variations in exon expression, i.e., eeQTLs, in different tissues.

Results Using whole genome and RNA sequence data from four tissues of over 200 cattle, sQTLs identified using exon inclusion ratios were verified by matching their effects on adjacent intron excision ratios. sQTLs contained the highest percentage of variants that are within the intronic region of genes and contained the lowest percentage of variants that are within intergenic regions, compared to eeQTLs and geQTLs. Many geQTLs and sQTLs are also detected as eeQTLs. Many expression QTLs, including sQTLs, were significant in all four tissues and had a similar effect in each tissue. To verify such expression QTL sharing between tissues, variants surrounding (±1Mb) the exon or gene were used to build local genomic relationship matrices (LGRM) and estimated genetic correlations between tissues. For many exons, the splicing and expression level was determined by the same cis additive genetic variance in different tissues. Thus, an effective but simple-to-implement meta-analysis combining information from three tissues is introduced to increase power to detect and validate sQTLs. sQTLs and eeQTLs together were more enriched for variants associated with cattle complex traits, compared to geQTLs. Several putative causal mutations were identified, including an sQTL at Chr6:87392580 within the 5th exon of kappa casein (CSN3) associated with milk production traits.

Conclusions Using novel analytical approaches, we report the first identification of numerous bovine sQTLs which are extensively shared between multiple tissue types. The significant overlaps between bovine sQTLs and complex traits QTL highlight the contribution of regulatory mutations to phenotypic variations.

Footnotes

  • Ruidong Xiang: ruidong.xiang{at}unimelb.edu.au;

    Ben J. Hayes: Ben.Hayes{at}ecodev.vic.gov.au;

    Christy J. Vander Jagt: Christy.VanderJagt{at}ecodev.vic.gov.au;

    Iona M. MacLeod: Iona.MacLeod{at}ecodev.vic.gov.au;

    Majid Khansefid: Majid.Khansefid{at}ecodev.vic.gov.au;

    Phil J. Bowman: P.Bowman{at}latrobe.edu.au;

    Zehu Yuan: zehu.yuan{at}ecodev.vic.gov.au;

    Claire P. Prowse-Wilkins: Claire.Prowse-Wilkins{at}ecodev.vic.gov.au;

    Coralie M. Reich: Coralie.Reich{at}ecodev.vic.gov.au;

    Brett A. Mason: Brett.Mason{at}ecodev.vic.gov.au;

    Josie B. Garner: Josie.Garner{at}ecodev.vic.gov.au;

    Leah C. Marett: Leah.Marett{at}ecodev.vic.gov.au;

    Yizhou Chen: yizhou.chen{at}dpi.nsw.gov.au;

    Sunduimijid Bolormaa: Bolormaa.Sunduimijid{at}ecodev.vic.gov.au;

    Hans D. Daetwyler: Hans.Daetwyler{at}ecodev.vic.gov.au;

    Amanda J. Chamberlain: Amanda.Chamberlain{at}ecodev.vic.gov.au;

    Michael E. Goddard: Mike.Goddard{at}ecodev.vic.gov.au;

  • List of abbreviations

    sQTLs
    splicing quantitative trait loci
    geQTLs
    gene expression quantitative trait loci
    eeQTLs
    exon expression quantitative trait loci
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    Posted April 05, 2018.
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    Genome variants associated with RNA splicing variation in bovine are extensively shared between tissues
    Ruidong Xiang, Ben J. Hayes, Christy J. Vander Jagt, Iona M. MacLeod, Majid Khansefid, Phil J. Bowman, Zehu Yuan, Claire P. Prowse-Wilkins, Coralie M. Reich, Brett A. Mason, Josie B. Garner, Leah C. Marett, Yizhou Chen, Sunduimijid Bolormaa, Hans D. Daetwyler, Amanda J. Chamberlain, Michael E. Goddard
    bioRxiv 220251; doi: https://doi.org/10.1101/220251
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    Genome variants associated with RNA splicing variation in bovine are extensively shared between tissues
    Ruidong Xiang, Ben J. Hayes, Christy J. Vander Jagt, Iona M. MacLeod, Majid Khansefid, Phil J. Bowman, Zehu Yuan, Claire P. Prowse-Wilkins, Coralie M. Reich, Brett A. Mason, Josie B. Garner, Leah C. Marett, Yizhou Chen, Sunduimijid Bolormaa, Hans D. Daetwyler, Amanda J. Chamberlain, Michael E. Goddard
    bioRxiv 220251; doi: https://doi.org/10.1101/220251

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