Extensive impact of low-frequency variants on the phenotypic landscape at population-scale
- Université de Strasbourg, CNRS, France
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.
Article and author information
Author details
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.
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Extensive impact of low-frequency variants on the phenotypic landscape at population-scale
eLife 8:e49258.
https://doi.org/10.7554/eLife.49258
Further reading
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- Genetics and Genomics
Rare genetic variants in yeast explain a large amount of phenotypic variation in a complex trait like growth.
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- Chromosomes and Gene Expression
- Genetics and Genomics
Models of nuclear genome organization often propose a binary division into active versus inactive compartments yet typically overlook nuclear bodies. Here, we integrated analysis of sequencing and image-based data to compare genome organization in four human cell types relative to three different nuclear locales: the nuclear lamina, nuclear speckles, and nucleoli. Although gene expression correlates mostly with nuclear speckle proximity, DNA replication timing correlates with proximity to multiple nuclear locales. Speckle attachment regions emerge as DNA replication initiation zones whose replication timing and gene composition vary with their attachment frequency. Most facultative LADs retain a partially repressed state as iLADs, despite their positioning in the nuclear interior. Knock out of two lamina proteins, Lamin A and LBR, causes a shift of H3K9me3-enriched LADs from lamina to nucleolus, and a reciprocal relocation of H3K27me3-enriched partially repressed iLADs from nucleolus to lamina. Thus, these partially repressed iLADs appear to compete with LADs for nuclear lamina attachment with consequences for replication timing. The nuclear organization in adherent cells is polarized with nuclear bodies and genomic regions segregating both radially and relative to the equatorial plane. Together, our results underscore the importance of considering genome organization relative to nuclear locales for a more complete understanding of the spatial and functional organization of the human genome.
