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Divergence of iron metabolism in wild Malaysian yeast.

Lee HN, Mostovoy Y, Hsu TY, Chang AH, Brem RB - G3 (Bethesda) (2013)

Bottom Line: Our findings support a model in which iron metabolism has diverged in Malaysian yeast as a consequence of a change in selective pressure, with Malaysian alleles shifting the dynamic range of iron response to low-iron concentrations and weakening resistance to extreme iron toxicity.By dissecting the iron scarcity specialist behavior of Malaysian yeast, our work highlights the power of expression divergence as a signpost for biologically and evolutionarily relevant variation at the organismal level.Interpreting the phenotypic relevance of gene expression variation is one of the primary challenges of modern genomics.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720.

ABSTRACT
Comparative genomic studies have reported widespread variation in levels of gene expression within and between species. Using these data to infer organism-level trait divergence has proven to be a key challenge in the field. We have used a wild Malaysian population of S. cerevisiae as a test bed in the search to predict and validate trait differences based on observations of regulatory variation. Malaysian yeast, when cultured in standard medium, activated regulatory programs that protect cells from the toxic effects of high iron. Malaysian yeast also showed a hyperactive regulatory response during culture in the presence of excess iron and had a unique growth defect in conditions of high iron. Molecular validation experiments pinpointed the iron metabolism factors AFT1, CCC1, and YAP5 as contributors to these molecular and cellular phenotypes; in genome-scale sequence analyses, a suite of iron toxicity response genes showed evidence for rapid protein evolution in Malaysian yeast. Our findings support a model in which iron metabolism has diverged in Malaysian yeast as a consequence of a change in selective pressure, with Malaysian alleles shifting the dynamic range of iron response to low-iron concentrations and weakening resistance to extreme iron toxicity. By dissecting the iron scarcity specialist behavior of Malaysian yeast, our work highlights the power of expression divergence as a signpost for biologically and evolutionarily relevant variation at the organismal level. Interpreting the phenotypic relevance of gene expression variation is one of the primary challenges of modern genomics.

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Regulatory impact of variation in AFT1, CCC1, and YAP5 between Malaysian and wine/European yeast. Each panel reports the regulatory effects of variation at iron metabolism genes in yeast cultured in one growth medium. In a given panel, each row reports comparisons between the effects of Malaysian and wine/European genotypes on expression of an iron starvation (Gasch et al. 2004) or iron resistance (Lin et al. 2011; Pimentel et al. 2012) target gene. Color in each cell represents a ratio of the expression measurements from two strains. A given cell in the first column reports the ratio, for the indicated target gene, of the expression in a homozygous Malaysian strain (UWOPS03.461.4), as a median across replicates (n = 2), to that in a homozygous wine/European strain (BC187). A given cell in each remaining column reports expression as a median across replicates in a Malaysian-wine/European hemizygote (UWOPS03.461.4 × BC187) bearing the Malaysian allele of the indicated variant locus (CCC1, n = 8; AFT1, n = 4; YAP5, n = 4) relative to the median expression in the hemizygote bearing the wine/European allele. (A) Iron starvation genes in synthetic complete medium. (B) Iron resistance genes in synthetic complete medium supplemented with 5 mM FeSO4. Values at the top of each column report the results of a paired Wilcoxon test for the significance of the differences in expression, across genes of the regulon, between the indicated genotypes. Individual replicate measurements are reported in Figure S2 and raw data are reported in File S7 and File S8.
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fig4: Regulatory impact of variation in AFT1, CCC1, and YAP5 between Malaysian and wine/European yeast. Each panel reports the regulatory effects of variation at iron metabolism genes in yeast cultured in one growth medium. In a given panel, each row reports comparisons between the effects of Malaysian and wine/European genotypes on expression of an iron starvation (Gasch et al. 2004) or iron resistance (Lin et al. 2011; Pimentel et al. 2012) target gene. Color in each cell represents a ratio of the expression measurements from two strains. A given cell in the first column reports the ratio, for the indicated target gene, of the expression in a homozygous Malaysian strain (UWOPS03.461.4), as a median across replicates (n = 2), to that in a homozygous wine/European strain (BC187). A given cell in each remaining column reports expression as a median across replicates in a Malaysian-wine/European hemizygote (UWOPS03.461.4 × BC187) bearing the Malaysian allele of the indicated variant locus (CCC1, n = 8; AFT1, n = 4; YAP5, n = 4) relative to the median expression in the hemizygote bearing the wine/European allele. (A) Iron starvation genes in synthetic complete medium. (B) Iron resistance genes in synthetic complete medium supplemented with 5 mM FeSO4. Values at the top of each column report the results of a paired Wilcoxon test for the significance of the differences in expression, across genes of the regulon, between the indicated genotypes. Individual replicate measurements are reported in Figure S2 and raw data are reported in File S7 and File S8.

Mentions: To analyze iron-toxicity response genes in Figure 1 and Table 2, we used the set of genes upregulated in a ccc1 laboratory strain, compared to wild-type, in 3 mM FeSO4 from (Lin et al. 2011). Expression analysis and sequence analysis were performed as described. For analysis of iron toxicity response factors in Figure 4 and Figure S2, we also mined the set of genes responsive to 2 mM FeSO4 in (Pimentel et al. 2012).


Divergence of iron metabolism in wild Malaysian yeast.

Lee HN, Mostovoy Y, Hsu TY, Chang AH, Brem RB - G3 (Bethesda) (2013)

Regulatory impact of variation in AFT1, CCC1, and YAP5 between Malaysian and wine/European yeast. Each panel reports the regulatory effects of variation at iron metabolism genes in yeast cultured in one growth medium. In a given panel, each row reports comparisons between the effects of Malaysian and wine/European genotypes on expression of an iron starvation (Gasch et al. 2004) or iron resistance (Lin et al. 2011; Pimentel et al. 2012) target gene. Color in each cell represents a ratio of the expression measurements from two strains. A given cell in the first column reports the ratio, for the indicated target gene, of the expression in a homozygous Malaysian strain (UWOPS03.461.4), as a median across replicates (n = 2), to that in a homozygous wine/European strain (BC187). A given cell in each remaining column reports expression as a median across replicates in a Malaysian-wine/European hemizygote (UWOPS03.461.4 × BC187) bearing the Malaysian allele of the indicated variant locus (CCC1, n = 8; AFT1, n = 4; YAP5, n = 4) relative to the median expression in the hemizygote bearing the wine/European allele. (A) Iron starvation genes in synthetic complete medium. (B) Iron resistance genes in synthetic complete medium supplemented with 5 mM FeSO4. Values at the top of each column report the results of a paired Wilcoxon test for the significance of the differences in expression, across genes of the regulon, between the indicated genotypes. Individual replicate measurements are reported in Figure S2 and raw data are reported in File S7 and File S8.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852381&req=5

fig4: Regulatory impact of variation in AFT1, CCC1, and YAP5 between Malaysian and wine/European yeast. Each panel reports the regulatory effects of variation at iron metabolism genes in yeast cultured in one growth medium. In a given panel, each row reports comparisons between the effects of Malaysian and wine/European genotypes on expression of an iron starvation (Gasch et al. 2004) or iron resistance (Lin et al. 2011; Pimentel et al. 2012) target gene. Color in each cell represents a ratio of the expression measurements from two strains. A given cell in the first column reports the ratio, for the indicated target gene, of the expression in a homozygous Malaysian strain (UWOPS03.461.4), as a median across replicates (n = 2), to that in a homozygous wine/European strain (BC187). A given cell in each remaining column reports expression as a median across replicates in a Malaysian-wine/European hemizygote (UWOPS03.461.4 × BC187) bearing the Malaysian allele of the indicated variant locus (CCC1, n = 8; AFT1, n = 4; YAP5, n = 4) relative to the median expression in the hemizygote bearing the wine/European allele. (A) Iron starvation genes in synthetic complete medium. (B) Iron resistance genes in synthetic complete medium supplemented with 5 mM FeSO4. Values at the top of each column report the results of a paired Wilcoxon test for the significance of the differences in expression, across genes of the regulon, between the indicated genotypes. Individual replicate measurements are reported in Figure S2 and raw data are reported in File S7 and File S8.
Mentions: To analyze iron-toxicity response genes in Figure 1 and Table 2, we used the set of genes upregulated in a ccc1 laboratory strain, compared to wild-type, in 3 mM FeSO4 from (Lin et al. 2011). Expression analysis and sequence analysis were performed as described. For analysis of iron toxicity response factors in Figure 4 and Figure S2, we also mined the set of genes responsive to 2 mM FeSO4 in (Pimentel et al. 2012).

Bottom Line: Our findings support a model in which iron metabolism has diverged in Malaysian yeast as a consequence of a change in selective pressure, with Malaysian alleles shifting the dynamic range of iron response to low-iron concentrations and weakening resistance to extreme iron toxicity.By dissecting the iron scarcity specialist behavior of Malaysian yeast, our work highlights the power of expression divergence as a signpost for biologically and evolutionarily relevant variation at the organismal level.Interpreting the phenotypic relevance of gene expression variation is one of the primary challenges of modern genomics.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720.

ABSTRACT
Comparative genomic studies have reported widespread variation in levels of gene expression within and between species. Using these data to infer organism-level trait divergence has proven to be a key challenge in the field. We have used a wild Malaysian population of S. cerevisiae as a test bed in the search to predict and validate trait differences based on observations of regulatory variation. Malaysian yeast, when cultured in standard medium, activated regulatory programs that protect cells from the toxic effects of high iron. Malaysian yeast also showed a hyperactive regulatory response during culture in the presence of excess iron and had a unique growth defect in conditions of high iron. Molecular validation experiments pinpointed the iron metabolism factors AFT1, CCC1, and YAP5 as contributors to these molecular and cellular phenotypes; in genome-scale sequence analyses, a suite of iron toxicity response genes showed evidence for rapid protein evolution in Malaysian yeast. Our findings support a model in which iron metabolism has diverged in Malaysian yeast as a consequence of a change in selective pressure, with Malaysian alleles shifting the dynamic range of iron response to low-iron concentrations and weakening resistance to extreme iron toxicity. By dissecting the iron scarcity specialist behavior of Malaysian yeast, our work highlights the power of expression divergence as a signpost for biologically and evolutionarily relevant variation at the organismal level. Interpreting the phenotypic relevance of gene expression variation is one of the primary challenges of modern genomics.

Show MeSH
Related in: MedlinePlus