Intragenic repeat expansion in the cell wall protein gene HPF1 controls yeast chronological aging
- Benjamin P. Barré1,
- Johan Hallin1,
- Jia-Xing Yue1,
- Karl Persson2,
- Ekaterina Mikhalev3,
- Agurtzane Irizar1,
- Sylvester Holt1,
- Dawn Thompson3,
- Mikael Molin4,
- Jonas Warringer2 and
- Gianni Liti1
- 1Université Côte d'Azur, CNRS, INSERM, IRCAN, 06107 Nice, France;
- 2Department of Chemistry and Molecular Biology, University of Gothenburg, 41390 Gothenburg, Sweden;
- 3Ginkgo Bioworks Incorporated, Boston, Massachusetts 02210, USA;
- 4Department of Biology and Biological Engineering, Chalmers University of Technology, 41296 Gothenburg, Sweden
Abstract
Aging varies among individuals due to both genetics and environment, but the underlying molecular mechanisms remain largely unknown. Using a highly recombined Saccharomyces cerevisiae population, we found 30 distinct quantitative trait loci (QTLs) that control chronological life span (CLS) in calorie-rich and calorie-restricted environments and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes but through different genetic variants. We tracked the two major QTLs to the cell wall glycoprotein genes FLO11 and HPF1. We found that massive expansion of intragenic tandem repeats within the N-terminal domain of HPF1 was sufficient to cause pronounced life span shortening. Life span impairment by HPF1 was buffered by rapamycin but not by calorie restriction. The HPF1 repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation altered methionine, lipid, and purine metabolism, and inhibited quiescence, which explains the life span shortening. We conclude that fast-evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular lifestyle and longevity.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.253351.119.
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Freely available online through the Genome Research Open Access option.
- Received June 5, 2019.
- Accepted April 9, 2020.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
