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Title: Repeated Cis-Regulatory Tuning of a Metabolic Bottleneck Gene during Evolution

Abstract

Repeated evolutionary events imply underlying genetic constraints that can make evolutionary mechanisms predictable. Morphological traits are thought to evolve frequently through cis-regulatory changes because these mechanisms bypass constraints in pleiotropic genes that are reused during development. In contrast, the constraints acting on metabolic traits during evolution are less well studied. Here we show how a metabolic bottleneck gene has repeatedly adopted similar cis-regulatory solutions during evolution, likely due to its pleiotropic role integrating flux from multiple metabolic pathways. Specifically, the genes encoding phosphoglucomutase activity (PGM1/PGM2), which connect GALactose catabolism to glycolysis, have gained and lost direct regulation by the transcription factor Gal4 several times during yeast evolution. Through targeted mutations of predicted Gal4-binding sites in yeast genomes, we show this galactose-mediated regulation of PGM1/2 supports vigorous growth on galactose in multiple yeast species, including Saccharomyces uvarum and Lachancea kluyveri. Furthermore, the addition of galactose-inducible PGM1 alone is sufficient to improve the growth on galactose of multiple species that lack this regulation, including Saccharomyces cerevisiae. The strong association between regulation of PGM1/2 by Gal4 even enables remarkably accurate predictions of galactose growth phenotypes between closely related species. This repeated mode of evolution suggests that this specific cis-regulatory connection is a commonmore » way that diverse yeasts can govern flux through the pathway, likely due to the constraints imposed by this pleiotropic bottleneck gene. Since metabolic pathways are highly interconnected, we argue that cis-regulatory evolution might be widespread at pleiotropic genes that control metabolic bottlenecks and intersections.« less

Authors:
 [1];  [1];  [1];  [2];  [1];  [1]
  1. Univ. of Wisconsin-Madison, Madison, WI (United States)
  2. DOE Joint Genome Institute, Walnut Creek, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Great Lakes Bioenergy Research Center, Madison, WI (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1560555
Alternate Identifier(s):
OSTI ID: 1459509
Grant/Contract Number:  
[AC02-05CH11231; SC0018409; FC02-07ER64494]
Resource Type:
Accepted Manuscript
Journal Name:
Molecular Biology and Evolution
Additional Journal Information:
[ Journal Volume: 35; Journal Issue: 8]; Journal ID: ISSN 0737-4038
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; cis-regulatory evolution; CRISPR/Cas9; galactose; metabolism; gene network; phosphoglucomutase

Citation Formats

Kuang, Meihua Christina, Kominek, Jacek, Alexander, William G., Cheng, Jan-Fang, Wrobel, Russell L., and Hittinger, Chris Todd. Repeated Cis-Regulatory Tuning of a Metabolic Bottleneck Gene during Evolution. United States: N. p., 2018. Web. doi:10.1093/molbev/msy102.
Kuang, Meihua Christina, Kominek, Jacek, Alexander, William G., Cheng, Jan-Fang, Wrobel, Russell L., & Hittinger, Chris Todd. Repeated Cis-Regulatory Tuning of a Metabolic Bottleneck Gene during Evolution. United States. doi:10.1093/molbev/msy102.
Kuang, Meihua Christina, Kominek, Jacek, Alexander, William G., Cheng, Jan-Fang, Wrobel, Russell L., and Hittinger, Chris Todd. Mon . "Repeated Cis-Regulatory Tuning of a Metabolic Bottleneck Gene during Evolution". United States. doi:10.1093/molbev/msy102. https://www.osti.gov/servlets/purl/1560555.
@article{osti_1560555,
title = {Repeated Cis-Regulatory Tuning of a Metabolic Bottleneck Gene during Evolution},
author = {Kuang, Meihua Christina and Kominek, Jacek and Alexander, William G. and Cheng, Jan-Fang and Wrobel, Russell L. and Hittinger, Chris Todd},
abstractNote = {Repeated evolutionary events imply underlying genetic constraints that can make evolutionary mechanisms predictable. Morphological traits are thought to evolve frequently through cis-regulatory changes because these mechanisms bypass constraints in pleiotropic genes that are reused during development. In contrast, the constraints acting on metabolic traits during evolution are less well studied. Here we show how a metabolic bottleneck gene has repeatedly adopted similar cis-regulatory solutions during evolution, likely due to its pleiotropic role integrating flux from multiple metabolic pathways. Specifically, the genes encoding phosphoglucomutase activity (PGM1/PGM2), which connect GALactose catabolism to glycolysis, have gained and lost direct regulation by the transcription factor Gal4 several times during yeast evolution. Through targeted mutations of predicted Gal4-binding sites in yeast genomes, we show this galactose-mediated regulation of PGM1/2 supports vigorous growth on galactose in multiple yeast species, including Saccharomyces uvarum and Lachancea kluyveri. Furthermore, the addition of galactose-inducible PGM1 alone is sufficient to improve the growth on galactose of multiple species that lack this regulation, including Saccharomyces cerevisiae. The strong association between regulation of PGM1/2 by Gal4 even enables remarkably accurate predictions of galactose growth phenotypes between closely related species. This repeated mode of evolution suggests that this specific cis-regulatory connection is a common way that diverse yeasts can govern flux through the pathway, likely due to the constraints imposed by this pleiotropic bottleneck gene. Since metabolic pathways are highly interconnected, we argue that cis-regulatory evolution might be widespread at pleiotropic genes that control metabolic bottlenecks and intersections.},
doi = {10.1093/molbev/msy102},
journal = {Molecular Biology and Evolution},
number = [8],
volume = [35],
place = {United States},
year = {2018},
month = {5}
}

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Figures / Tables:

FIG. 1 FIG. 1: Diagram of the GAL network in the budding yeast model S. cerevisiae and the role of Gal4-binding sites in explaining quantitative variation in growth on galactose. In the absence of galactose, the transcription factor Gal4 is inhibited by the corepressor Gal80, which prevents the expression of the GALactosemore » utilization genes. When galactose is present, Gal80 is sequestered by the co-inducer Gal3, allowing Gal4 to induce GAL gene expression. Other GAL genes encode the transporter Gal2 and three enzymes in the Leloir pathway that catabolize galactose. Glucose-1-phosphate, the end product of the Leloir pathway, is converted by the phosphoglucomutases Pgm1/2 into glucose-6-phosphate, which then enters glycolysis. For each protein, except for Gal2 (where paralogous hexose transporters complicated analyses), the correlation (R2) between the number of predicted Gal4-binding sites upstream of the gene encoding it and growth on galactose across diverse yeast species (see fig. 2) is colorcoded according to the key.« less

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