Genetics of trans-regulatory variation in gene expression

  1. Frank Wolfgang Albert  Is a corresponding author
  2. Joshua S Bloom  Is a corresponding author
  3. Jake Siegel
  4. Laura Day
  5. Leonid Kruglyak  Is a corresponding author
  1. University of Minnesota, United States
  2. University of California, Los Angeles, United States

Abstract

Heritable variation in gene expression forms a crucial bridge between genomic variation and the biology of many traits. However, most expression quantitative trait loci (eQTLs) remain unidentified. We mapped eQTLs by transcriptome sequencing in 1,012 yeast segregants. The resulting eQTLs accounted for over 70% of the heritability of mRNA levels, allowing comprehensive dissection of regulatory variation. Most genes had multiple eQTLs. Most expression variation arose from trans-acting eQTLs distant from their target genes. Nearly all trans-eQTLs clustered at 102 hotspot locations, some of which influenced the expression of thousands of genes. Fine-mapped hotspot regions were enriched for transcription factor genes. While most genes had a local eQTL, most of these had no detectable effects on the expression of other genes in trans. Hundreds of non-additive genetic interactions accounted for small fractions of expression variation. These results reveal the complexity of genetic influences on transcriptome variation in unprecedented depth and detail.

Data availability

Sequencing reads have been deposited at SRA under accession codes SRP148919 and SRP149494. Processed datasets are included with this manuscript, and are also available in a FigShare repository at https://figshare.com/s/83bddc1ddf3f97108ad4. All data are available freely and without restriction.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Frank Wolfgang Albert

    Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, United States
    For correspondence
    falbert@umn.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1380-8063
  2. Joshua S Bloom

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    jbloom@mednet.ucla.edu
    Competing interests
    No competing interests declared.
  3. Jake Siegel

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  4. Laura Day

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  5. Leonid Kruglyak

    Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    LKruglyak@mednet.ucla.edu
    Competing interests
    Leonid Kruglyak, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8065-3057

Funding

Howard Hughes Medical Institute (Investigator)

  • Leonid Kruglyak

National Institute of General Medical Sciences (R01GM102308)

  • Leonid Kruglyak

National Institute of General Medical Sciences (1R35GM124676-01)

  • Frank Wolfgang Albert

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

Copyright

© 2018, Albert 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.

Metrics

  • 9,703
    views
  • 972
    downloads
  • 160
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Frank Wolfgang Albert
  2. Joshua S Bloom
  3. Jake Siegel
  4. Laura Day
  5. Leonid Kruglyak
(2018)
Genetics of trans-regulatory variation in gene expression
eLife 7:e35471.
https://doi.org/10.7554/eLife.35471

Share this article

https://doi.org/10.7554/eLife.35471

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Bhumil Patel, Maryke Grobler ... Needhi Bhalla
    Research Article

    Meiotic crossover recombination is essential for both accurate chromosome segregation and the generation of new haplotypes for natural selection to act upon. This requirement is known as crossover assurance and is one example of crossover control. While the conserved role of the ATPase, PCH-2, during meiotic prophase has been enigmatic, a universal phenotype when pch-2 or its orthologs are mutated is a change in the number and distribution of meiotic crossovers. Here, we show that PCH-2 controls the number and distribution of crossovers by antagonizing their formation. This antagonism produces different effects at different stages of meiotic prophase: early in meiotic prophase, PCH-2 prevents double-strand breaks from becoming crossover-eligible intermediates, limiting crossover formation at sites of initial double-strand break formation and homolog interactions. Later in meiotic prophase, PCH-2 winnows the number of crossover-eligible intermediates, contributing to the designation of crossovers and ultimately, crossover assurance. We also demonstrate that PCH-2 accomplishes this regulation through the meiotic HORMAD, HIM-3. Our data strongly support a model in which PCH-2’s conserved role is to remodel meiotic HORMADs throughout meiotic prophase to destabilize crossover-eligible precursors and coordinate meiotic recombination with synapsis, ensuring the progressive implementation of meiotic recombination and explaining its function in the pachytene checkpoint and crossover control.

    1. Cancer Biology
    2. Chromosomes and Gene Expression
    Ashley L Cook, Surojit Sur ... Nicolas Wyhs
    Research Article

    Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high-throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD in human cells. This screen implicated disruption of kinase SMG1’s phosphorylation of UPF1 as a potential disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from human and murine truncating mutations in vitro and murine cells in vivo. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable human leukocyte antigens (HLA) class I-associated peptides from NMD-downregulated proteins on the surface of human cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases.