Letter | Published:

Genetic variants regulating expression levels and isoform diversity during embryogenesis

Nature volume 541, pages 402406 (19 January 2017) | Download Citation

Abstract

Embryonic development is driven by tightly regulated patterns of gene expression, despite extensive genetic variation among individuals. Studies of expression quantitative trait loci1,2,3,4 (eQTL) indicate that genetic variation frequently alters gene expression in cell-culture models and differentiated tissues5,6. However, the extent and types of genetic variation impacting embryonic gene expression, and their interactions with developmental programs, remain largely unknown. Here we assessed the effect of genetic variation on transcriptional (expression levels) and post-transcriptional (3′ RNA processing) regulation across multiple stages of metazoan development, using 80 inbred Drosophila wild isolates7, identifying thousands of developmental-stage-specific and shared QTL. Given the small blocks of linkage disequilibrium in Drosophila7,8,9, we obtain near base-pair resolution, resolving causal mutations in developmental enhancers, validated transcription-factor-binding sites and RNA motifs. This fine-grain mapping uncovered extensive allelic interactions within enhancers that have opposite effects, thereby buffering their impact on enhancer activity. QTL affecting 3′ RNA processing identify new functional motifs leading to transcript isoform diversity and changes in the lengths of 3′ untranslated regions. These results highlight how developmental stage influences the effects of genetic variation and uncover multiple mechanisms that regulate and buffer expression variation during embryogenesis.

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Acknowledgements

This work was supported technically by the European Molecular Biology Laboratory (EMBL) Genomics Core facility, and financially by the European Research Council (ERC; FP/2007-2013), ERC advanced grant CisRegVar to E.E.M.F., EMBL predoctoral funds to E.E.M.F. and E.B.

Author information

Author notes

    • Enrico Cannavò
    •  & Nils Koelling

    These authors contributed equally to this work.

Affiliations

  1. European Molecular Biology Laboratory (EMBL), Genome Biology Unit, D-69117 Heidelberg, Germany

    • Enrico Cannavò
    • , Dermot Harnett
    • , David Garfield
    • , Lucia Ciglar
    • , Hilary E. Gustafson
    • , Rebecca R. Viales
    • , Raquel Marco-Ferreres
    • , Jacob F. Degner
    • , Bingqing Zhao
    •  & Eileen E. M. Furlong
  2. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton CB10 1SD, UK

    • Nils Koelling
    • , Francesco P. Casale
    • , Oliver Stegle
    •  & Ewan Birney

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Contributions

E.E.M.F., E.B., E.C. and N.K. designed the study, explored results and prepared the manuscript, with contributions from all authors. E.C. led the experiments with help from L.C., H.E.G., R.R.V., R.M.-F. and B.Z. N.K. led the data processing and QTL calling, with help from F.P.C., J.F.D. and O.S. D.H. led the biological analysis, with input from D.G and N.K.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ewan Birney or Eileen E. M. Furlong.

Reviewer Information Nature thanks S. Celniker and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature20802

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