Evidence for widespread adaptive evolution of gene expression in budding yeast

Fraser, Hunter B.; Moses, Alan M.; Schadt, Eric E.

doi:10.1073/pnas.0912245107

Cited by 157 publications

(197 citation statements)

References 26 publications

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“…In all 66 of these SNPs, the rarer allele resulted in a faster death rate (increased sensitivity to ER stress) (Dataset S5). This observation implies that natural selection is a likely factor driving the distribution of allelic effects (24,25). Seven of the 66 SNPs are nonsynonymous coding changes in Xbp1 (1 SNP), Megator (1 SNP), CG33339 (4 SNPs), and CG11873 (1 SNP) (Dataset S5).…”

Section: Resultsmentioning

confidence: 99%

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Chow

Wolfner

Clark

2013

Proc. Natl. Acad. Sci. U.S.A.

111

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Natural genetic variation is a rich resource for identifying novel elements of cellular pathways such as endoplasmic reticulum (ER) stress. ER stress occurs when misfolded proteins accumulate in the ER and cells respond with the conserved unfolded protein response (UPR), which includes large-scale gene expression changes. Although ER stress can be a cause or a modifying factor of human disease, little is known of the amount of variation in the response to ER stress and the genes contributing to such variation. To study natural variation in ER stress response in a model system, we measured the survival time in response to tunicamycin-induced ER stress in flies from 114 lines from the sequenced Drosophila Genetic Reference Panel of wildderived inbred strains. These lines showed high heterogeneity in survival time under ER stress conditions. To identify the genes that may be driving this phenotypic variation, we profiled ER stressinduced gene expression and performed an association study. Microarray analysis identified variation in transcript levels of numerous known and previously unknown ER stress-responsive genes. Survival time was significantly associated with polymorphisms in candidate genes with known (i.e., Xbp1) and unknown roles in ER stress. Functional testing found that 17 of 25 tested candidate genes from the association study have putative roles in ER stress. In both approaches, one-third of ER stress genes had human orthologs that contribute to human disease. This study establishes Drosophila as a useful model for studying variation in ER stress and identifying ER stress genes that may contribute to human disease.

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Section: Resultsmentioning

confidence: 99%

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Chow

Wolfner

Clark

2013

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Furthermore, the directionality of the outcome of any perturbation of genes in a network such as whether the perturbation will raise or lower a phenotypic outcome depends on the genetic background and environmental conditions due to complex network feedbacks (Davey Smith and Ebrahim 2003;Chen et al 2008). Last but not least, confounding effects from pleiotropy and LD can complicate causality inference, and the interpretation of causality results can be further complicated by factors such as morphogenic stability, developmental adaptation, and canalization (Davey Smith and Ebrahim 2003;Schadt et al 2005;Fraser et al 2010). Therefore, some of the conclusions should be interpreted with care, and more follow-up studies are needed to test the hypothesis put forward.…”

Section: à5mentioning

confidence: 99%

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

Yang¹,

Zhang²,

Molony³

et al. 2010

Genome Res.

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240

226

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Liver cytochrome P450s (P450s) play critical roles in drug metabolism, toxicology, and metabolic processes. Despite rapid progress in the understanding of these enzymes, a systematic investigation of the full spectrum of functionality of individual P450s, the interrelationship or networks connecting them, and the genetic control of each gene/enzyme is lacking. To this end, we genotyped, expression-profiled, and measured P450 activities of 466 human liver samples and applied a systems biology approach via the integration of genetics, gene expression, and enzyme activity measurements. We found that most P450s were positively correlated among themselves and were highly correlated with known regulators as well as thousands of other genes enriched for pathways relevant to the metabolism of drugs, fatty acids, amino acids, and steroids. Genome-wide association analyses between genetic polymorphisms and P450 expression or enzyme activities revealed sets of SNPs associated with P450 traits, and suggested the existence of both cis-regulation of P450 expression (especially for CYP2D6) and more complex trans-regulation of P450 activity. Several novel SNPs associated with CYP2D6 expression and enzyme activity were validated in an independent human cohort. By constructing a weighted coexpression network and a Bayesian regulatory network, we defined the human liver transcriptional network structure, uncovered subnetworks representative of the P450 regulatory system, and identified novel candidate regulatory genes, namely, EHHADH, SLC10A1, and AKR1D1. The P450 subnetworks were then validated using gene signatures responsive to ligands of known P450 regulators in mouse and rat. This systematic survey provides a comprehensive view of the functionality, genetic control, and interactions of P450s.

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“…Previous studies indicate that the architecture of biological networks is conserved through evolution (24)(25)(26), suggesting that the overall wiring diagram may be somewhat robust to changes in the contexts. If so, context-dependent risk variants will more likely induce changes to the network activity potentially by increasing or decreasing the number of edges and nodes in the network, thereby perturbing the molecular processes and biological functions defined by that network.…”

Section: Defining Inherited Risk Dependent On Environmentsmentioning

confidence: 99%

NEW: Network-Enabled Wisdom in Biology, Medicine, and Health Care

2012

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Complete repertoires of molecular activity in and between tissues provided by new high-dimensional "omics" technologies hold great promise for characterizing human physiology at all levels of biological hierarchies. The combined effects of genetic and environmental perturbations at any level of these hierarchies can lead to vicious cycles of pathology and complex systemic diseases. The challenge lies in extracting all relevant information from the rapidly increasing volumes of omics data and translating this information first into knowledge and ultimately into wisdom that can yield clinically actionable results. Here, we discuss how molecular networks are central to the implementation of this new biology in medicine and translation to preventive and personalized health care.

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Evidence for widespread adaptive evolution of gene expression in budding yeast

Cited by 157 publications

References 26 publications

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Using natural variation in Drosophila to discover previously unknown endoplasmic reticulum stress genes

Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver

NEW: Network-Enabled Wisdom in Biology, Medicine, and Health Care

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