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The effect of genetic variation on promoter usage and enhancer activity

Author

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  • Marco Garieri

    (University of Geneva
    Institute of Genetics and Genomics in Geneva
    Swiss Institute of Bioinformatics, SIB, UNIL Sorge)

  • Olivier Delaneau

    (University of Geneva
    Institute of Genetics and Genomics in Geneva
    Swiss Institute of Bioinformatics, SIB, UNIL Sorge)

  • Federico Santoni

    (University of Geneva
    University Hospitals of Geneva, Service of Genetic Medicine)

  • Richard J. Fish

    (University of Geneva)

  • David Mull

    (University of Geneva)

  • Piero Carninci

    (Division of Genomic Technologies, RIKEN Center for Life Science Technologies)

  • Emmanouil T. Dermitzakis

    (University of Geneva
    Institute of Genetics and Genomics in Geneva
    Swiss Institute of Bioinformatics, SIB, UNIL Sorge)

  • Stylianos E. Antonarakis

    (University of Geneva
    Institute of Genetics and Genomics in Geneva
    University Hospitals of Geneva, Service of Genetic Medicine)

  • Alexandre Fort

    (University of Geneva)

Abstract

The identification of genetic variants affecting gene expression, namely expression quantitative trait loci (eQTLs), has contributed to the understanding of mechanisms underlying human traits and diseases. The majority of these variants map in non-coding regulatory regions of the genome and their identification remains challenging. Here, we use natural genetic variation and CAGE transcriptomes from 154 EBV-transformed lymphoblastoid cell lines, derived from unrelated individuals, to map 5376 and 110 regulatory variants associated with promoter usage (puQTLs) and enhancer activity (eaQTLs), respectively. We characterize five categories of genes associated with puQTLs, distinguishing single from multi-promoter genes. Among multi-promoter genes, we find puQTL effects either specific to a single promoter or to multiple promoters with variable effect orientations. Regulatory variants associated with opposite effects on different mRNA isoforms suggest compensatory mechanisms occurring between alternative promoters. Our analyses identify differential promoter usage and modulation of enhancer activity as molecular mechanisms underlying eQTLs related to regulatory elements.

Suggested Citation

  • Marco Garieri & Olivier Delaneau & Federico Santoni & Richard J. Fish & David Mull & Piero Carninci & Emmanouil T. Dermitzakis & Stylianos E. Antonarakis & Alexandre Fort, 2017. "The effect of genetic variation on promoter usage and enhancer activity," Nature Communications, Nature, vol. 8(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01467-7
    DOI: 10.1038/s41467-017-01467-7
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    Cited by:

    1. Zhao Wang & Qian Liang & Xinyi Qian & Bolang Hu & Zhanye Zheng & Jianhua Wang & Yuelin Hu & Zhengkai Bao & Ke Zhao & Yao Zhou & Xiangling Feng & Xianfu Yi & Jin Li & Jiandang Shi & Zhe Liu & Jihui Hao, 2023. "An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    2. Jiapei Yuan & Yang Tong & Le Wang & Xiaoxiao Yang & Xiaochuan Liu & Meng Shu & Zekun Li & Wen Jin & Chenchen Guan & Yuting Wang & Qiang Zhang & Yang Yang, 2024. "A compendium of genetic variations associated with promoter usage across 49 human tissues," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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