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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- Developmental Biology
- Genetics and Genomics
Paternal obesity has been implicated in adult-onset metabolic disease in offspring. However, the molecular mechanisms driving these paternal effects and the developmental processes involved remain poorly understood. One underexplored possibility is the role of paternally induced effects on placenta development and function. To address this, we investigated paternal high-fat diet-induced obesity in relation to sperm histone H3 lysine 4 tri-methylation signatures, the placenta transcriptome, and cellular composition. C57BL6/J male mice were fed either a control or high-fat diet for 10 weeks beginning at 6 weeks of age. Males were timed-mated with control-fed C57BL6/J females to generate pregnancies, followed by collection of sperm, and placentas at embryonic day (E)14.5. Chromatin immunoprecipitation targeting histone H3 lysine 4 tri-methylation (H3K4me3) followed by sequencing (ChIP-seq) was performed on sperm to define obesity-associated changes in enrichment. Paternal obesity corresponded with altered sperm H3K4me3 at promoters of genes involved in metabolism and development. Notably, altered sperm H3K4me3 was also localized at placental enhancers. Bulk RNA-sequencing on placentas revealed paternal obesity-associated sex-specific changes in expression of genes involved in hypoxic processes such as angiogenesis, nutrient transport, and imprinted genes, with a subset of de-regulated genes showing changes in H3K4me3 in sperm at corresponding promoters. Paternal obesity was also linked to impaired placenta development; specifically, a deconvolution analysis revealed altered trophoblast cell lineage specification. These findings implicate paternal obesity effects on placenta development and function as one potential developmental route to offspring metabolic disease.
