Genetic Interactions Between Transcription Factors Cause Natural Variation in Yeast

Gerke, Justin P.; Lorenz, Kimberly; Cohen, Barak A.

doi:10.1126/science.1166426

Cited by 202 publications

(252 citation statements)

References 44 publications

(38 reference statements)

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“…Thus, pathways enriched for nonsynonymous polymorphism across S. cerevisiae may shed light on the changes in the life history of this species since its divergence from S. bayanus. In addition, some cases of pathway-level polymorphism may result from divergence between S. cerevisiae populations, as the result of adaptation (36,37) or of relaxed selection in particular niches. Improved sequence sampling of the well-defined populations in this species (30) ultimately will enable in-depth study of the changes in selective pressure at play during their divergence.…”

Section: Discussionmentioning

confidence: 99%

Polygenic and directional regulatory evolution across pathways in Saccharomyces

Bullard

Mostovoy

Dudoit

et al. 2010

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

140

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The search to understand how genomes innovate in response to selection dominates the field of evolutionary biology. Powerful molecular evolution approaches have been developed to test individual loci for signatures of selection. In many cases, however, an organism's response to changes in selective pressure may be mediated by multiple genes, whose products function together in a cellular process or pathway. Here we assess the prevalence of polygenic evolution in pathways in the yeasts Saccharomyces cerevisiae and S. bayanus. We first established short-read sequencing methods to detect cis-regulatory variation in a diploid hybrid between the species. We then tested for the scenario in which selective pressure in one species to increase or decrease the activity of a pathway has driven the accumulation of cis-regulatory variants that act in the same direction on gene expression. Application of this test revealed a variety of yeast pathways with evidence for directional regulatory evolution. In parallel, we also used population genomic sequencing data to compare protein and cis-regulatory variation within and between species. We identified pathways with evidence for divergence within S. cerevisiae, and we detected signatures of positive selection between S. cerevisiae and S. bayanus. Our results point to polygenic, pathway-level change as a common evolutionary mechanism among yeasts. We suggest that pathway analyses, including our test for directional regulatory evolution, will prove to be a relevant and powerful strategy in many evolutionary genomic applications.A main challenge of evolutionary biology is to understand the influence of selection on genetic variation within and between species. Classically, molecular evolution methods have targeted individual genes or loci for tests of selection. Their successes have uncovered both protein-coding and regulatory variants with signatures of non-neutral evolution (1-3). However, decades of quantitative genetic mapping studies indicate that in most cases, variation in phenotype between individuals is the result of multiple sequence changes at unlinked loci (4). The genetic response to changes in selective pressure is likely to follow the same pattern, but, to date, methods for identifying cases of polygenic evolution have been at a premium.Some of the strongest evidence for polygenic adaptation has emerged from the study of protein-coding variants between phylogenetic lineages. Signatures of positive selection can be detected in the protein-coding sequences of groups of genes of related function (5-8), suggestive of a coherent series of genetic changes accumulated by a population in response to selection. Additionally, genetic variation in gene expression represents a rich data source for signatures of selection, both positive (9, 10) and purifying (11,12), although the mechanisms that govern regulatory evolution are not fully understood. Regulatory variants can act in cis, to impact the expression of a neighboring gene, or in trans, targeting the expression of genes el...

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Section: Discussionmentioning

confidence: 99%

Polygenic and directional regulatory evolution across pathways in Saccharomyces

Bullard

Mostovoy

Dudoit

et al. 2010

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

140

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“…For instance, Lemos et al (2008) and Graze et al (2009) found a significant association between dominance for gene expression and variants in trans-acting elements in Drosophila. Moreover, trans effects could be responsible for many phenotypic differences, as reported in yeast (Gerke et al, 2009). Among the hybrids of the Rupert, Laval and domestic brook charr, we previously found important differences in the mode of gene expression inheritance relative to the parental populations.…”

Section: Cis-acting Regulatory Effectsmentioning

confidence: 99%

Linking transcriptomic and genomic variation to growth in brook charr hybrids (Salvelinus fontinalis, Mitchill)

Bougas¹,

Normandeau²,

Audet³

et al. 2013

Heredity

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Hybridization can lead to phenotypic differences arising from changes in gene expression patterns or new allele combinations. Variation in gene expression is thought to be controlled by differences in transcription regulation of parental alleles, either through cis-or trans-regulatory elements. A previous study among brook charr hybrids from different populations (Rupert, Laval, and domestic) showing distinct length at age during early life stages also revealed different patterns in transcription regulation inheritance of transcript abundance. In the present study, transcript abundance using RNA-sequencing and quantitative real-time PCR, single-nucleotide polymorphism (SNP) genotypes and allelic imbalance were assessed in order to understand the molecular mechanisms underlying the observed transcriptomic and differences in length at age among domestic Â Rupert hybrids and Laval Â domestic hybrids. We found 198 differentially expressed genes between the two hybrid crosses, and allelic imbalance could be analyzed for 69 of them. Among these 69 genes, 36 genes exhibited cis-acting regulatory effects in both of the two crosses, thus confirming the prevalent role of cis-acting regulatory elements in the regulation of differentially expressed genes among intraspecific hybrids. In addition, we detected a significant association between SNP genotypes of three genes and length at age. Our study is thus one of the few that have highlighted some of the molecular mechanisms potentially involved in the differential phenotypic expression in intraspecific hybrids for nonmodel species.

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“…Single‐SNP analyses may miss such a complexity, primarily because if a genetic factor operates through a mechanism involving multiple genes, and is also affected by environmental factors, the single investigation may not examine statistical interactions between loci that are informative about the biological and biochemical pathways underpinning the phenotype. On the contrary, SNP interactions may carry more information about the phenotype than those observed from individual SNPs alone (Gerke, Lorenz & Cohen, 2009; Su et al., 2015). Assessing SNP‐SNP interactions at the gene level co‐occurring within a specific phenotype and not due to linkage disequilibrium (LD) can overcome this problem, possibly finding specific subprocesses more strongly associated with the phenotype than single‐SNP analysis (Cordell, 2009).…”

Section: Introductionmentioning

confidence: 99%

The genetic component of human longevity: New insights from the analysis of pathway‐based SNP‐SNP interactions

et al. 2018

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SummaryIn human longevity studies, single nucleotide polymorphism (SNP) analysis identified a large number of genetic variants with small effects, yet not easily replicable in different populations. New insights may come from the combined analysis of different SNPs, especially when grouped by metabolic pathway. We applied this approach to study the joint effect on longevity of SNPs belonging to three candidate pathways, the insulin/insulin‐like growth factor signalling (IIS), DNA repair and pro/antioxidant. We analysed data from 1,058 tagging SNPs in 140 genes, collected in 1825 subjects (1,089 unrelated nonagenarians from the Danish 1905 Birth Cohort Study and 736 Danish controls aged 46–55 years) for evaluating synergic interactions by SNPsyn. Synergies were further tested by the multidimensional reduction (MDR) approach, both intra‐ and interpathways. The best combinations (FDR<0.0001) resulted those encompassing IGF1R‐rs12437963 and PTPN1‐rs6067484, TP53‐rs2078486 and ERCC2‐rs50871, TXNRD1‐rs17202060 and TP53‐rs2078486, the latter two supporting a central role of TP53 in mediating the concerted activation of the DNA repair and pro‐antioxidant pathways in human longevity. Results were consistently replicated with both approaches, as well as a significant effect on longevity was found for the GHSR gene, which also interacts with partners belonging to both IIS and DNA repair pathways (PAPPA,PTPN1,PARK7, MRE11A). The combination GHSR‐MREA11, positively associated with longevity by MDR, was further found influencing longitudinal survival in nonagenarian females (p = .026). Results here presented highlight the validity of SNP‐SNP interactions analyses for investigating the genetics of human longevity, confirming previously identified markers but also pointing to novel genes as central nodes of additional networks involved in human longevity.

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Genetic Interactions Between Transcription Factors Cause Natural Variation in Yeast

Cited by 202 publications

References 44 publications

Polygenic and directional regulatory evolution across pathways in Saccharomyces

Polygenic and directional regulatory evolution across pathways in Saccharomyces

Linking transcriptomic and genomic variation to growth in brook charr hybrids (Salvelinus fontinalis, Mitchill)

The genetic component of human longevity: New insights from the analysis of pathway‐based SNP‐SNP interactions

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