The metabolic domestication syndrome of budding yeast

The famous model organism -Saccharomyces cerevisiaeis widely present in a variety of natural and human-associated habitats. Despite extensive studies of this organism, the metabolic mechanisms driving its adaptation to varying niches remain elusive. We here gathered genomic resources from 1,807S. cerevisiaestrains and assembled them into a high-quality pan-genome, facilitating the comprehensive characterization of genetic diversity across isolates. Utilizing the pan-genome, 1,807 strain-specific genome-scale metabolic models (ssGEMs) were generated, which performed well in quantitative predictions of cellular phenotypes, thus helping to examine the metabolic disparities among allS. cerevisiaestrains. Integrative analyses of fluxomic and transcriptomics with ssGEMs showcased the ubiquitous transcriptional regulation in certain metabolic sub-pathways (i.e., amino acid synthesis) at a population level. Additionally, the gene/reaction loss analysis through the ssGEMs refined by transcriptomics showed thatS. cerevisiaestrains from various ecological niches had undergone reductive evolution at both the genomic and metabolic network levels when compared to wild isolates. Finally, the compiled analyses of the pan-genome, transcriptome, and metabolic fluxome revealed remarkable metabolic differences amongS. cerevisiaestrains originating from distinct oxygen-limited niches, including human gut and cheese environments, and identified convergent metabolic evolution, such as downregulation of oxidative phosphorylation pathways. Together, these results illustrate how yeast adapts to distinct niches modulated by genomic and metabolic reprogramming, and provide computational resources for translating yeast genotype to fitness in future studies.

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Massively parallel experimental interrogation of natural variants in ancient signaling pathways reveals both purifying selection and local adaptation

Aguilar-Rodríguez,

Vila,

Chen

et al. 2024

Preprint

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The nature of standing genetic variation remains a central debate in population genetics, with differing perspectives on whether common variants are mostly neutral or have functional effects. We address this question by directly mapping the fitness effects of over 9,000 natural variants in the Ras/PKA and TOR/Sch9 pathways—key regulators of cell proliferation in eukaryotes—across four conditions inSaccharomyces cerevisiae. While many variants are neutral in our assay, on the order of 3,500 exhibited significant fitness effects. These non-neutral variants tend to be missense and affect conserved, more densely packed, and less solvent-exposed protein regions. They are also typically younger, occur at lower frequencies, and more often found in heterozygous states, suggesting they are subject to purifying selection. A substantial fraction of non-neutral variants showing strong fitness effects in our experiments, however, is present at high frequencies in the population. These variants show signs of local adaptation as they tend to be found specifically in domesticated strains adapted to human-made environments. Our findings support the view that while common variants are often neutral, a significant proportion have adaptive functional consequences and are driven into the population by local positive selection. This study highlights the potential to explore the functional effects of natural genetic variation on a genome scale with quantitative fitness measurements in the laboratory, bridging the gap between population genetics and functional genomics to understand evolutionary dynamics in the wild.

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The metabolic domestication syndrome of budding yeast

Cited by 4 publications

References 78 publications

Metabolomes evolve faster than metabolic network structures

Metabolomes evolve faster than metabolic network structures

Yeast adapts to diverse ecological niches driven by genomics and metabolic reprogramming

Massively parallel experimental interrogation of natural variants in ancient signaling pathways reveals both purifying selection and local adaptation

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