Extensive impact of low-frequency variants on the phenotypic landscape at population-scale

Abstract

Genome-wide association studies (GWAS) allow to dissect complex traits and map genetic variants, which often explain relatively little of the heritability. One potential reason is the preponderance of undetected low-frequency variants. To increase their allele frequency and assess their phenotypic impact in a population, we generated a diallel panel of 3,025 yeast hybrids, derived from pairwise crosses between natural isolates and examined a large number of traits. Parental versus hybrid regression analysis showed that while most phenotypic variance is explained by additivity, a third is governed by non-additive effects, with complete dominance having a key role. By performing GWAS on the diallel panel, we found that associated variants with low frequency in the initial population are overrepresented and explain a fraction of the phenotypic variance as well as an effect size similar to common variants. Overall, we highlighted the relevance of low frequency variants on the phenotypic variation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 and 4.

The following previously published data sets were used

Article and author information

Author details

  1. Téo Fournier

    Department of Genetics, Genomics and Microbiology, Université de Strasbourg, CNRS, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4860-6728
  2. Omar Abou Saada

    Department of Genetics, Genomics and Microbiology, Université de Strasbourg, CNRS, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Jing Hou

    Department of Genetics, Genomics and Microbiology, Université de Strasbourg, CNRS, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Jackson Peter

    Department of Genetics, Genomics and Microbiology, Université de Strasbourg, CNRS, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Elodie Caudal

    Department of Genetics, Genomics and Microbiology, Université de Strasbourg, CNRS, Strasbourg, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Joseph Schacherer

    Department of Genetics, Genomics and Microbiology, Université de Strasbourg, CNRS, Strasbourg, France
    For correspondence
    schacherer@unistra.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6606-6884

Funding

National Institutes of Health (R01 GM101091-01)

  • Joseph Schacherer

European Research Council (Consolidator grants (772505))

  • Joseph Schacherer

Fondation pour la Recherche Médicale (Graduate student grant)

  • Téo Fournier

Institut Universitaire de France

  • Joseph Schacherer

University of Strasbourg Institute for Advanced Study

  • Joseph Schacherer

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

Copyright

© 2019, Fournier 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.

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. Téo Fournier
  2. Omar Abou Saada
  3. Jing Hou
  4. Jackson Peter
  5. Elodie Caudal
  6. Joseph Schacherer
(2019)
Extensive impact of low-frequency variants on the phenotypic landscape at population-scale
eLife 8:e49258.
https://doi.org/10.7554/eLife.49258

Share this article

https://doi.org/10.7554/eLife.49258

Further reading

    1. Genetics and Genomics
    Luisa F Pallares
    Insight

    Rare genetic variants in yeast explain a large amount of phenotypic variation in a complex trait like growth.

    1. Genetics and Genomics
    2. Microbiology and Infectious Disease
    Iti Mehta, Jacob B Hogins ... Larry Reitzer
    Research Article

    Polyamines are biologically ubiquitous cations that bind to nucleic acids, ribosomes, and phospholipids and, thereby, modulate numerous processes, including surface motility in Escherichia coli. We characterized the metabolic pathways that contribute to polyamine-dependent control of surface motility in the commonly used strain W3110 and the transcriptome of a mutant lacking a putrescine synthetic pathway that was required for surface motility. Genetic analysis showed that surface motility required type 1 pili, the simultaneous presence of two independent putrescine anabolic pathways, and modulation by putrescine transport and catabolism. An immunological assay for FimA—the major pili subunit, reverse transcription quantitative PCR of fimA, and transmission electron microscopy confirmed that pili synthesis required putrescine. Comparative RNAseq analysis of a wild type and ΔspeB mutant which exhibits impaired pili synthesis showed that the latter had fewer transcripts for pili structural genes and for fimB which codes for the phase variation recombinase that orients the fim operon promoter in the ON phase, although loss of speB did not affect the promoter orientation. Results from the RNAseq analysis also suggested (a) changes in transcripts for several transcription factor genes that affect fim operon expression, (b) compensatory mechanisms for low putrescine which implies a putrescine homeostatic network, and (c) decreased transcripts of genes for oxidative energy metabolism and iron transport which a previous genetic analysis suggests may be sufficient to account for the pili defect in putrescine synthesis mutants. We conclude that pili synthesis requires putrescine and putrescine concentration is controlled by a complex homeostatic network that includes the genes of oxidative energy metabolism.