Environmental robustness of the global yeast genetic interaction network

Costanzo, Michael; Hou, Jing; Messier, Vincent; Nelson, J. Daniel; Rahman, Mahfuzur; VanderSluis, Benjamin; Wang, Wen; Pons, Carles; Ross, Catherine; Ušaj, Matej; Luis, Bryan Joseph San; Shuteriqi, Emira; Koch, Elizabeth N.; Aloy, Patrick; Myers, Chad L.; Boone, Charles; Andrews, Brenda

doi:10.1126/science.abf8424

Cited by 57 publications

(52 citation statements)

References 69 publications

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“…Second, gene essentiality significantly impacts gene connectivity: essential genes are more densely connected than nonessential genes (Fig. 2), consistent with observations from single-organism genetic networks (Mnaimneh et al 2004;Costanzo et al 2010Costanzo et al , 2016Costanzo et al , 2021. This finding suggests that genes more important to cellular function are more likely central hubs in the coevolution network.…”

Section: Discussionsupporting

confidence: 83%

“…The inferred gene coevolution network provides a hierarchical view of cellular function from bioprocesses to pathways. Interpolation of the gene coevolution network with of fitness assay data from singleand digenic S. cerevisiae mutants (Costanzo et al 2010(Costanzo et al , 2016(Costanzo et al , 2021Usaj et al 2017) provides insight into subnetwork-and gene-specific potential to buffer genetic perturbations. Mapping the gene coevolution network onto the chromosomes of two model yeast genomes uncovers extensive inter-chromosomal and long-range intra-chromosomal associations, providing an 'entangled' view of the genome.…”

Section: Introductionmentioning

confidence: 99%

“…Interpolation of the gene coevolution network with of fitness assay data from single-and digenic S. cerevisiae mutants (Costanzo et al 2010(Costanzo et al , 2016(Costanzo et al , 2021Usaj et al 2017) provides insight into subnetwork-and ortholog-specific potential to buffer genetic perturbations. Surprisingly, comparisons of genetic networks inferred from gene coevolution and genetic interactions yield similar functional insights; for example, hubs of genes tend to be functionally related and gene essentiality impacts gene connectivity wherein essential genes are more densely connected than non-essential genes.…”

Section: Introductionmentioning

confidence: 99%

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An orthologous gene coevolution network provides insight into eukaryotic cellular and genomic structure and function

Steenwyk

Phillips

Yang

et al. 2021

Preprint

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Gene coevolution—which refers to gene pairs whose evolutionary rates covary across speciation events—is often observed among functionally related genes. We present a comprehensive gene coevolution network inferred from the examination of nearly three million gene pairs from 332 budding yeast species spanning ~400 million years of eukaryotic evolution. Modules within the network provide insight into cellular and genomic structure and function, such as genetic pleiotropy, genes functioning in distinct cellular compartments, vesicle transport, and DNA replication. Examination of the phenotypic impact of network perturbation across 14 environmental conditions using deletion mutant data from the baker’s yeast Saccharomyces cerevisiae suggests that fitness in diverse environments is impacted by gene neighborhood and gene connectivity. By mapping the network onto the chromosomes of S. cerevisiae and the opportunistic human pathogen Candida albicans, which diverged ~235 million years ago, we discovered that coevolving gene pairs are not clustered in either species; rather, they are most often located on different chromosomes or far apart on the same chromosome. The budding yeast gene coevolution network captures the hierarchy of eukaryotic cellular structure and function, provides a roadmap for genotype-to-phenotype discovery, and portrays the genome as an extensively linked ensemble of genes.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An orthologous gene coevolution network provides insight into eukaryotic cellular and genomic structure and function

Steenwyk

Phillips

Yang

et al. 2021

Preprint

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“…In this study, we have generated a combinatorial CRISPR library targeting the human SLC25 transporters, the largest known protein family for mitochondrial metabolite transport, with the goal of exploring pairwise genetic interactions and their dependence on metabolic environment. The functional redundancy and conditional essentiality underscores the need for a combinatorial approach for the SLC25 transporters, as has been demonstrated for other SLC families 58 and the need to explore different nutrient conditions 63,64 . By screening across four different media conditions, we both recovered known interactions and discovered unanticipated insights into mitochondrial micronutrient and cofactor biology.…”

Section: Discussionmentioning

confidence: 99%

Combinatorial G x G x E CRISPR screening and functional analysis highlights SLC25A39 in mitochondrial GSH transport

Shi

Reimer

Shah

et al. 2021

Preprint

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The SLC25 carrier family consists of 53 transporters that shuttle nutrients and co-factors across mitochondrial membranes. The family is highly redundant and their transport activities coupled to metabolic state. Here, we introduce a pooled, dual CRISPR screening strategy that knocks out pairs of transporters in four metabolic states- glucose, galactose, OXPHOS inhibition, and absence of pyruvate-designed to unmask the inter-dependence of these genes. In total, we screened 63 genes in four metabolic states, corresponding to 2016 single and pair-wise genetic perturbations. We recovered 19 gene-by-environment (GxE) interactions and 9 gene-by-gene (GxG) interactions. One GxE interaction hit illustrated that the fitness defect in the mitochondrial folate carrier (SLC25A32) KO cells was genetically buffered in galactose due to a lack of substrate in de novo purine biosynthesis. Another GxE interaction hit revealed non-equivalence of the paralogous ATP/ADP exchangers (ANTs) with ANT2 specifically required during OXPHOS inhibition. GxG analysis highlighted a buffering interaction between the iron transporter SLC25A37 and the poorly characterized SLC25A39. Mitochondrial metabolite profiling, organelle transport assays, and structure-guided mutagenesis suggests SLC25A39 is critical for mitochondrial glutathione (GSH) transport. Our work underscores the importance of systemetically investigating family-wide genetic interactions between mitochondrial transporters across many metabolic environments.

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“…At a reductionist level, living organisms are comprised of networks of interacting biochemical pathways (Costanzo et al, 2021). Thermodynamics dictates that the rate of biochemical reactions depends on the temperature of the system.…”

Section: Introductionmentioning

confidence: 99%

Plasticity of Performance Curves in Ectotherms: Individual Variation Modulates Population Responses to Environmental Change

Seebacher

Little

2021

Front. Physiol.

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Many ectothermic animals can respond to changes in their environment by altering the sensitivities of physiological rates, given sufficient time to do so. In other words, thermal acclimation and developmental plasticity can shift thermal performance curves so that performance may be completely or partially buffered against the effects of environmental temperature changes. Plastic responses can thereby increase the resilience to temperature change. However, there may be pronounced differences between individuals in their capacity for plasticity, and these differences are not necessarily reflected in population means. In a bet-hedging strategy, only a subsection of the population may persist under environmental conditions that favour either plasticity or fixed phenotypes. Thus, experimental approaches that measure means across individuals can not necessarily predict population responses to temperature change. Here, we collated published data of 608 mosquitofish (Gambusia holbrooki) each acclimated twice, to a cool and a warm temperature in random order, to model how diversity in individual capacity for plasticity can affect populations under different temperature regimes. The persistence of both plastic and fixed phenotypes indicates that on average, neither phenotype is selectively more advantageous. Fish with low acclimation capacity had greater maximal swimming performance in warm conditions, but their performance decreased to a greater extent with decreasing temperature in variable environments. In contrast, the performance of fish with high acclimation capacity decreased to a lesser extent with a decrease in temperature. Hence, even though fish with low acclimation capacity had greater maximal performance, high acclimation capacity may be advantageous when ecologically relevant behaviour requires submaximal locomotor performance. Trade-offs, developmental effects and the advantages of plastic phenotypes together are likely to explain the observed population variation.

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Environmental robustness of the global yeast genetic interaction network

Cited by 57 publications

References 69 publications

An orthologous gene coevolution network provides insight into eukaryotic cellular and genomic structure and function

An orthologous gene coevolution network provides insight into eukaryotic cellular and genomic structure and function

Combinatorial G x G x E CRISPR screening and functional analysis highlights SLC25A39 in mitochondrial GSH transport

Plasticity of Performance Curves in Ectotherms: Individual Variation Modulates Population Responses to Environmental Change

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