Intragenic repeat expansion in the cell wall protein gene HPF1 controls yeast chronological aging
Journal article, 2020

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.


Benjamin P. Barré


Johan Hallin


Jia Xing Yue


Karl Persson

University of Gothenburg

Ekaterina Mikhalev

Ginkgo Bioworks

Agurtzane Irizar


Sylvester Holt


Dawn Thompson

Ginkgo Bioworks

Mikael Molin

Chalmers, Biology and Biological Engineering, Systems and Synthetic Biology

Jonas Warringer

University of Gothenburg

Gianni Liti


Genome Research

1088-9051 (ISSN) 1549-5469 (eISSN)

Vol. 30 5 697-710

Subject Categories

Cell Biology

Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)






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