1. Genetics and Genomics
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Alternative polyadenylation mediates genetic regulation of gene expression

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Cite this article as: eLife 2020;9:e57492 doi: 10.7554/eLife.57492

Abstract

Little is known about co-transcriptional or post-transcriptional regulatory mechanisms linking noncoding variation to variation in organismal traits. To begin addressing this gap, we used 3' Seq to study the impact of genetic variation on alternative polyadenylation (APA) in the nuclear and total mRNA fractions of 52 HapMap Yoruba human lymphoblastoid cell lines. We mapped 602 APA quantitative trait loci (apaQTLs) at 10% FDR, of which 152 were nuclear specific. Effect sizes at intronic apaQTLs are negatively correlated with eQTL effect sizes. These observations suggest genetic variants can decrease mRNA expression levels by increasing usage of intronic PAS. We also identified 24 apaQTLs associated with protein levels, but not mRNA expression. Finally, we found that 19% of apaQTLs can be associated with disease. Thus, our work demonstrates that APA links genetic variation to variation in gene expression, protein expression, and disease risk, and reveals uncharted modes of genetic regulation.

Data availability

Fastq files and PAS annotations are available at GEO under accession GSE138197. All reproducible scripts and software versions can be found at through Zenodo with doi:10.5281/zenodo.3905372

The following data sets were generated

Article and author information

Author details

  1. Briana E Mittleman

    Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4979-4652
  2. Sebastian Pott

    Department of Human Genetics, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4118-6150
  3. Shane Warland

    Section of Genetic Medicine, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Tony Zeng

    Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zepeng Mu

    Genetics, Genomics, and Systems Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7717-3247
  6. Mayher Kaur

    Section of Genetic Medicine, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Yoav Gilad

    Department of Medicine, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8284-8926
  8. Yang Li

    Department of Medicine, Department of Human Genetics, University of Chicago, Chicago, United States
    For correspondence
    yangili1@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0736-251X

Funding

National Institutes of Health (T32 GM09197)

  • Briana E Mittleman

National Institutes of Health (F31HL149259)

  • Briana E Mittleman

National Institutes of Health (R01GM130738)

  • Yang Li

National Institutes of Health (K12 HL119995)

  • Sebastian Pott

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Gene W Yeo, University of California, San Diego, United States

Publication history

  1. Received: April 20, 2020
  2. Accepted: June 17, 2020
  3. Accepted Manuscript published: June 25, 2020 (version 1)
  4. Version of Record published: July 6, 2020 (version 2)

Copyright

© 2020, Mittleman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

    1. Epidemiology and Global Health
    2. Genetics and Genomics
    Mohd Anisul et al.
    Research Article Updated

    Background:

    The virus SARS-CoV-2 can exploit biological vulnerabilities (e.g. host proteins) in susceptible hosts that predispose to the development of severe COVID-19.

    Methods:

    To identify host proteins that may contribute to the risk of severe COVID-19, we undertook proteome-wide genetic colocalisation tests, and polygenic (pan) and cis-Mendelian randomisation analyses leveraging publicly available protein and COVID-19 datasets.

    Results:

    Our analytic approach identified several known targets (e.g. ABO, OAS1), but also nominated new proteins such as soluble Fas (colocalisation probability >0.9, p=1 × 10-4), implicating Fas-mediated apoptosis as a potential target for COVID-19 risk. The polygenic (pan) and cis-Mendelian randomisation analyses showed consistent associations of genetically predicted ABO protein with several COVID-19 phenotypes. The ABO signal is highly pleiotropic, and a look-up of proteins associated with the ABO signal revealed that the strongest association was with soluble CD209. We demonstrated experimentally that CD209 directly interacts with the spike protein of SARS-CoV-2, suggesting a mechanism that could explain the ABO association with COVID-19.

    Conclusions:

    Our work provides a prioritised list of host targets potentially exploited by SARS-CoV-2 and is a precursor for further research on CD209 and FAS as therapeutically tractable targets for COVID-19.

    Funding:

    MAK, JSc, JH, AB, DO, MC, EMM, MG, ID were funded by Open Targets. J.Z. and T.R.G were funded by the UK Medical Research Council Integrative Epidemiology Unit (MC_UU_00011/4). JSh and GJW were funded by the Wellcome Trust Grant 206194. This research was funded in part by the Wellcome Trust [Grant 206194]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission.

    1. Genetics and Genomics
    Clara Bouyx et al.
    Research Article Updated

    Fungal adhesins (Als) or flocculins are family of cell surface proteins that mediate adhesion to diverse biotic and abiotic surfaces. A striking characteristic of Als proteins originally identified in the pathogenic Candida albicans is to form functional amyloids that mediate cis-interaction leading to the formation of adhesin nanodomains and trans-interaction between amyloid sequences of opposing cells. In this report, we show that flocculins encoded by FLO11 in Saccharomyces cerevisiae behave like adhesins in C. albicans. To do so, we show that the formation of nanodomains under an external physical force requires a threshold number of amyloid-forming sequences in the Flo11 protein. Then, using a genome editing approach, we constructed strains expressing variants of the Flo11 protein under the endogenous FLO11 promoter, leading to the demonstration that the loss of amyloid-forming sequences strongly reduces cell-cell interaction but has no effect on either plastic adherence or invasive growth in agar, both phenotypes being dependent on the N- and C-terminal ends of Flo11p. Finally, we show that the location of Flo11 is not altered either by the absence of amyloid-forming sequences or by the removal of the N- or C-terminus of the protein.