Cis- and trans-regulatory contributions to a hierarchy of factors influencing gene expression variation
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ABSTRACT:
ORGANISM(S): Drosophila simulans Drosophila simulans x Drosophila sechellia Drosophila sechellia
PROVIDER: GSE280534 | GEO | 2024/11/07
REPOSITORIES: GEO
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Project description:Determining the different sources of heritable variation underlying quantitative traits in nature is currently at the forefront of genetic studies. To this end, molecular profiling studies in S. cerevisiae have shown that individual gene expression levels are subject to genetic control and this variation can mediate genetic differences on phenotype. Thus, determining how natural variation influences allele specific expression (ASE) and ultimately complex traits represents a useful tool to determine the mechanisms leading to yeast niche adaptation. Here, in order to test the hypothesis that allele-specific expression differences between isolates contributes to the phenotypic diversity in natural populations, we evaluated ASE levels in a grid of six F1 hybrids from the cross of four representative founder strains from major lineages. Genome-wide and across hybrids we quantified ASE for 3,320 genes. We found evidence for abundant genome-wide expression differences between alleles, with levels ranging between 27% up to 61% of the evaluated genes, depending on the cross. We observed that ASE can be explained by allele-specific differences in transcription factor binding to cis-regulatory regions and differences in strain-specific trans-activation can be detected by taking advantage of the shared trans environment of F1 hybrids. Furthermore, modules of genes under cis-regulatory variation with related function are enriched within the different genetic backgrounds, supporting the premise of intraspecies directional regulatory selection in yeast. Finally, we were able to identify two genes, GDB1 and ASN1 exhibiting high expression levels in the Wine/European strain and underlying phenotypic differences for oenological phenotypes due to polymorphisms within non-coding regions, providing direct evidence of the importance of regulatory variation in natural trait diversity.
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Project description:Gene expression is regulated both by cis elements, which are DNA segments closely linked to the genes they regulate, and by trans activating factors, which are usually proteins capable of diffusing to unlinked genes. Understanding the patterns and sources of regulatory variation is crucial for understanding phenotypic and genome evolution. Here, we investigate the global patterns of gene expression evolution in Saccharomyces cerivisiae. We report statistical methods useful in quantifying cis and trans regulation using next generation sequencing data. Using these methods, measured genome-wide allele-specific expression by deep sequencing to investigate the genetic architecture of gene regulatory variation between two strains of Saccharomyces cerevisiae. We find that expression polymorphism in yeast is common for both cis and trans regulation, though trans variation is more common. Our detailed analyses of the effects of functional constraint on expression variation as indicated by measures such as protein connectivity, gene essentiality, and the ratio of nonsynonymous substitutions to synonymous substitutions clearly reveal that both classes of variation are under purifying selection, but trans variation is more sensitive to selective constraint. Comparing interspecific expression divergence between S. cerevisiae and S. paradoxus to our intraspecific variation suggests that natural selection strongly influences the patterns of variation we observe. Further analyses revealed that cis divergence is more frequently mediated by positive Darwinian selection than trans divergence, which is compatible with neutral evolution.
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Project description:Gene expression is regulated both by cis elements, which are DNA segments closely linked to the genes they regulate, and by trans activating factors, which are usually proteins capable of diffusing to unlinked genes. Understanding the patterns and sources of regulatory variation is crucial for understanding phenotypic and genome evolution. Here, we investigate the global patterns of gene expression evolution in Saccharomyces cerivisiae. We report statistical methods useful in quantifying cis and trans regulation using next generation sequencing data. Using these methods, measured genome-wide allele-specific expression by deep sequencing to investigate the genetic architecture of gene regulatory variation between two strains of Saccharomyces cerevisiae. We find that expression polymorphism in yeast is common for both cis and trans regulation, though trans variation is more common. Our detailed analyses of the effects of functional constraint on expression variation as indicated by measures such as protein connectivity, gene essentiality, and the ratio of nonsynonymous substitutions to synonymous substitutions clearly reveal that both classes of variation are under purifying selection, but trans variation is more sensitive to selective constraint. Comparing interspecific expression divergence between S. cerevisiae and S. paradoxus to our intraspecific variation suggests that natural selection strongly influences the patterns of variation we observe. Further analyses revealed that cis divergence is more frequently mediated by positive Darwinian selection than trans divergence, which is compatible with neutral evolution. Study the gene expression patterns in two strains of yeast (BY and RM)
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Project description:Noncoding genetic variation is a major driver of phenotypic diversity but determining the underlying mechanisms and the cell types in which it acts remain challenging problems. Here, we investigate the impact of natural genetic variation provided by phenotypically diverse inbred strains of mice on gene expression and epigenetic landscapes of Kupffer cells. Analysis of gene expression in Kupffer cells and other liver cell types derived from C57BL/6J, BALB/cJ and A/J mice provided evidence for strain-specific differences in environmental factors influencing Kupffer cell phenotypes, including preferential Leptin signaling in BALB/cJ Kupffer cells. Systematic analysis of transcriptomic and epigenetic data from F1 hybrids of these mice, and transcriptomic data from strain-specific Kupffer cells engrafted into a common host enabled quantitative assessment of cis versus trans effects of genetic variation on gene expression and an estimate of cell autonomous versus non cell autonomous effects. Under homeostatic conditions, trans effects of genetic variation were dominant, with the majority of trans regulation being non cell autonomous. In contrast, strain specific responses to acutely administered LPS were primarily associated with genetic variation acting in cis to modify response elements for lineage determining and signal dependent transcription factors. Collectively, these findings reveal cell intrinsic and environmental effects of natural genetic variation on gene expression, demonstrate the use of enhancers as detectors of trans effects of genetic variation, and provide a new resource for understanding the impact of genetic variation on gene expression in Kupffer cells.
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