1. Chromosomes and Gene Expression
  2. Genetics and Genomics

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
https://doi.org/10.7554/eLife.35471
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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

  • 9,630
    views
  • 968
    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

Categories and tags

Research organism

Further reading

    1. Chromosomes and Gene Expression

    Sir2 and Fun30 regulate ribosomal DNA replication timing via MCM helicase positioning and nucleosome occupancy

    Carmina Lichauco, Eric J Foss ... Antonio Bedalov
    Research Article

    The association between late replication timing and low transcription rates in eukaryotic heterochromatin is well known, yet the specific mechanisms underlying this link remain uncertain. In Saccharomyces cerevisiae, the histone deacetylase Sir2 is required for both transcriptional silencing and late replication at the repetitive ribosomal DNA (rDNA) arrays. We have previously reported that in the absence of SIR2, a de-repressed RNA PolII repositions MCM replicative helicases from their loading site at the ribosomal origin, where they abut well-positioned, high-occupancy nucleosomes, to an adjacent region with lower nucleosome occupancy. By developing a method that can distinguish activation of closely spaced MCM complexes, here we show that the displaced MCMs at rDNA origins have increased firing propensity compared to the nondisplaced MCMs. Furthermore, we found that both activation of the repositioned MCMs and low occupancy of the adjacent nucleosomes critically depend on the chromatin remodeling activity of FUN30. Our study elucidates the mechanism by which Sir2 delays replication timing, and it demonstrates, for the first time, that activation of a specific replication origin in vivo relies on the nucleosome context shaped by a single chromatin remodeler.

    1. Chromosomes and Gene Expression

    Cryogenic Electron Microscopy: MagIC beads for scarce macromolecules

    Carlos Moreno-Yruela, Beat Fierz
    Insight

    Specialized magnetic beads that bind target proteins to a cryogenic electron microscopy grid make it possible to study the structure of protein complexes from dilute samples.

    1. Chromosomes and Gene Expression
    2. Structural Biology and Molecular Biophysics

    Surprising features of nuclear receptor interaction networks revealed by live-cell single-molecule imaging

    Liza Dahal, Thomas GW Graham ... Xavier Darzacq
    Research Article

    Type II nuclear receptors (T2NRs) require heterodimerization with a common partner, the retinoid X receptor (RXR), to bind cognate DNA recognition sites in chromatin. Based on previous biochemical and overexpression studies, binding of T2NRs to chromatin is proposed to be regulated by competition for a limiting pool of the core RXR subunit. However, this mechanism has not yet been tested for endogenous proteins in live cells. Using single-molecule tracking (SMT) and proximity-assisted photoactivation (PAPA), we monitored interactions between endogenously tagged RXR and retinoic acid receptor (RAR) in live cells. Unexpectedly, we find that higher expression of RAR, but not RXR, increases heterodimerization and chromatin binding in U2OS cells. This surprising finding indicates the limiting factor is not RXR but likely its cadre of obligate dimer binding partners. SMT and PAPA thus provide a direct way to probe which components are functionally limiting within a complex TF interaction network providing new insights into mechanisms of gene regulation in vivo with implications for drug development targeting nuclear receptors.