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Evolution of a membrane protein regulon in Saccharomyces.

Martin HC, Roop JI, Schraiber JG, Hsu TY, Brem RB - Mol. Biol. Evol. (2012)

Bottom Line: In a survey of gene regulons with expression divergence between Saccharomyces cerevisiae and S. paradoxus, we found that most were subject to variation in trans-regulatory factors that provided no evidence against a neutral model.For this membrane protein group, S. paradoxus alleles at regulatory loci were associated with elevated expression and altered stress responsiveness relative to other yeasts.Our results support a model in which a distinct expression program for the membrane protein genes in S. paradoxus has been preferentially maintained by negative selection as the result of an increased importance to organismal fitness.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, USA.

ABSTRACT
Expression variation is widespread between species. The ability to distinguish regulatory change driven by natural selection from the consequences of neutral drift remains a major challenge in comparative genomics. In this work, we used observations of mRNA expression and promoter sequence to analyze signatures of selection on groups of functionally related genes in Saccharomycete yeasts. In a survey of gene regulons with expression divergence between Saccharomyces cerevisiae and S. paradoxus, we found that most were subject to variation in trans-regulatory factors that provided no evidence against a neutral model. However, we identified one regulon of membrane protein genes controlled by unlinked cis- and trans-acting determinants with coherent effects on gene expression, consistent with a history of directional, nonneutral evolution. For this membrane protein group, S. paradoxus alleles at regulatory loci were associated with elevated expression and altered stress responsiveness relative to other yeasts. In a phylogenetic comparison of promoter sequences of the membrane protein genes between species, the S. paradoxus lineage was distinguished by a short branch length, indicative of strong selective constraint. Likewise, sequence variants within the S. paradoxus population, but not across strains of other yeasts, were skewed toward low frequencies in promoters of genes in the membrane protein regulon, again reflecting strong purifying selection. Our results support a model in which a distinct expression program for the membrane protein genes in S. paradoxus has been preferentially maintained by negative selection as the result of an increased importance to organismal fitness. These findings illustrate the power of integrating expression- and sequence-based tests of natural selection in the study of evolutionary forces that underlie regulatory change.

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Directional regulatory change between Saccharomycetes in the membrane protein regulon. Each colored element represents regulatory changes between Saccharomyces cerevisiae and S. paradoxus in rich-medium (Tirosh et al. 2009) at one membrane protein gene, overlaid on a cartoon localization of the encoded protein. P, proportion of randomly sampled gene groups showing regulatory changes whose directions were at least as coherent as those observed in the membrane regulon (table 1). (A) Signs of cis-regulatory effects. Orange, the allele from S. paradoxus was the most highly expressed in an interspecific hybrid; blue, the S. cerevisiae allele was most highly expressed. (B) Signs of trans-regulatory effects, which derive from expression measurements of interspecific hybrids and of parental strains grown independently (Tirosh et al. 2009). Orange, the regulatory allele from S. paradoxus was associated with higher expression; blue, the S. cerevisiae allele was associated with higher expression.
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Figure 1: Directional regulatory change between Saccharomycetes in the membrane protein regulon. Each colored element represents regulatory changes between Saccharomyces cerevisiae and S. paradoxus in rich-medium (Tirosh et al. 2009) at one membrane protein gene, overlaid on a cartoon localization of the encoded protein. P, proportion of randomly sampled gene groups showing regulatory changes whose directions were at least as coherent as those observed in the membrane regulon (table 1). (A) Signs of cis-regulatory effects. Orange, the allele from S. paradoxus was the most highly expressed in an interspecific hybrid; blue, the S. cerevisiae allele was most highly expressed. (B) Signs of trans-regulatory effects, which derive from expression measurements of interspecific hybrids and of parental strains grown independently (Tirosh et al. 2009). Orange, the regulatory allele from S. paradoxus was associated with higher expression; blue, the S. cerevisiae allele was associated with higher expression.

Mentions: To investigate the role of nonneutral evolutionary forces underlying expression variation between S. cerevisiae and S. paradoxus, we focused on a set of genes mediating membrane protein trafficking and function and membrane lipid composition (fig. 1 and supplementary table 1, Supplementary Material online). This gene group showed strong evidence for coherent regulatory change of cis-acting factors and of those acting in trans (reaching a significance level in each case where <0.1 group would be expected under the ; table 1). For both cis- and trans-acting determinants of expression of this gene group, the S. paradoxus allele at the respective locus conferred high expression relative to that of S. cerevisiae (fig. 1), a pattern of reinforcement between the two mechanisms of regulatory change rarely observed in data (resampling P = 0.04; see Materials and Methods). The presence of many unlinked cis-regulatory variants between species acting in the same direction is unlikely under a neutral model (Bullard et al. 2010), and indicative of a change in selective pressure on the regulation of the membrane protein set. Additionally, the reinforcement between cis- and trans-mediated changes impinging on this regulon provides evidence against a model in which compensatory variants in a given species have arisen, in regulators and their targets, to preserve a constant degree of DNA-binding activity or transcription.Fig. 1.


Evolution of a membrane protein regulon in Saccharomyces.

Martin HC, Roop JI, Schraiber JG, Hsu TY, Brem RB - Mol. Biol. Evol. (2012)

Directional regulatory change between Saccharomycetes in the membrane protein regulon. Each colored element represents regulatory changes between Saccharomyces cerevisiae and S. paradoxus in rich-medium (Tirosh et al. 2009) at one membrane protein gene, overlaid on a cartoon localization of the encoded protein. P, proportion of randomly sampled gene groups showing regulatory changes whose directions were at least as coherent as those observed in the membrane regulon (table 1). (A) Signs of cis-regulatory effects. Orange, the allele from S. paradoxus was the most highly expressed in an interspecific hybrid; blue, the S. cerevisiae allele was most highly expressed. (B) Signs of trans-regulatory effects, which derive from expression measurements of interspecific hybrids and of parental strains grown independently (Tirosh et al. 2009). Orange, the regulatory allele from S. paradoxus was associated with higher expression; blue, the S. cerevisiae allele was associated with higher expression.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3375471&req=5

Figure 1: Directional regulatory change between Saccharomycetes in the membrane protein regulon. Each colored element represents regulatory changes between Saccharomyces cerevisiae and S. paradoxus in rich-medium (Tirosh et al. 2009) at one membrane protein gene, overlaid on a cartoon localization of the encoded protein. P, proportion of randomly sampled gene groups showing regulatory changes whose directions were at least as coherent as those observed in the membrane regulon (table 1). (A) Signs of cis-regulatory effects. Orange, the allele from S. paradoxus was the most highly expressed in an interspecific hybrid; blue, the S. cerevisiae allele was most highly expressed. (B) Signs of trans-regulatory effects, which derive from expression measurements of interspecific hybrids and of parental strains grown independently (Tirosh et al. 2009). Orange, the regulatory allele from S. paradoxus was associated with higher expression; blue, the S. cerevisiae allele was associated with higher expression.
Mentions: To investigate the role of nonneutral evolutionary forces underlying expression variation between S. cerevisiae and S. paradoxus, we focused on a set of genes mediating membrane protein trafficking and function and membrane lipid composition (fig. 1 and supplementary table 1, Supplementary Material online). This gene group showed strong evidence for coherent regulatory change of cis-acting factors and of those acting in trans (reaching a significance level in each case where <0.1 group would be expected under the ; table 1). For both cis- and trans-acting determinants of expression of this gene group, the S. paradoxus allele at the respective locus conferred high expression relative to that of S. cerevisiae (fig. 1), a pattern of reinforcement between the two mechanisms of regulatory change rarely observed in data (resampling P = 0.04; see Materials and Methods). The presence of many unlinked cis-regulatory variants between species acting in the same direction is unlikely under a neutral model (Bullard et al. 2010), and indicative of a change in selective pressure on the regulation of the membrane protein set. Additionally, the reinforcement between cis- and trans-mediated changes impinging on this regulon provides evidence against a model in which compensatory variants in a given species have arisen, in regulators and their targets, to preserve a constant degree of DNA-binding activity or transcription.Fig. 1.

Bottom Line: In a survey of gene regulons with expression divergence between Saccharomyces cerevisiae and S. paradoxus, we found that most were subject to variation in trans-regulatory factors that provided no evidence against a neutral model.For this membrane protein group, S. paradoxus alleles at regulatory loci were associated with elevated expression and altered stress responsiveness relative to other yeasts.Our results support a model in which a distinct expression program for the membrane protein genes in S. paradoxus has been preferentially maintained by negative selection as the result of an increased importance to organismal fitness.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, USA.

ABSTRACT
Expression variation is widespread between species. The ability to distinguish regulatory change driven by natural selection from the consequences of neutral drift remains a major challenge in comparative genomics. In this work, we used observations of mRNA expression and promoter sequence to analyze signatures of selection on groups of functionally related genes in Saccharomycete yeasts. In a survey of gene regulons with expression divergence between Saccharomyces cerevisiae and S. paradoxus, we found that most were subject to variation in trans-regulatory factors that provided no evidence against a neutral model. However, we identified one regulon of membrane protein genes controlled by unlinked cis- and trans-acting determinants with coherent effects on gene expression, consistent with a history of directional, nonneutral evolution. For this membrane protein group, S. paradoxus alleles at regulatory loci were associated with elevated expression and altered stress responsiveness relative to other yeasts. In a phylogenetic comparison of promoter sequences of the membrane protein genes between species, the S. paradoxus lineage was distinguished by a short branch length, indicative of strong selective constraint. Likewise, sequence variants within the S. paradoxus population, but not across strains of other yeasts, were skewed toward low frequencies in promoters of genes in the membrane protein regulon, again reflecting strong purifying selection. Our results support a model in which a distinct expression program for the membrane protein genes in S. paradoxus has been preferentially maintained by negative selection as the result of an increased importance to organismal fitness. These findings illustrate the power of integrating expression- and sequence-based tests of natural selection in the study of evolutionary forces that underlie regulatory change.

Show MeSH
Related in: MedlinePlus