Natural variations in yeast aging reveal genetic and environmental factors

Abstract : Aging is a classical complex trait varying quantitatively among individuals and affected by both the genetic background and the environment. While aging is the highest risk factor for a large number of diseases, little is known about the underlying molecular mechanisms. Identifying the causal genetic variants underlying natural variation in longevity and understanding their interaction with the genetic background and the environment remains a major challenge. In this work, I used the budding yeast, Saccharomyces cerevisiae, to identify environmental and genetic factors contributing to aging. While extensive classical genetic studies discovered several genes involved in the regulation of chronological lifespan (CLS), which measures cell viability dynamic in non-dividing condition, using laboratory strains in standard conditions, there are only few studies exploiting variations in natural populations. In the first part, I used a large cohort of more than 1000 sequenced natural S. cerevisiae strains to provide a species-wide overview of CLS variability. Longevity was measured in different environments, including calorie restriction (CR), a natural intervention known to increase lifespan, and in the presence of rapamycin (RM), a drug that mimics CR by downregulating the TOR pathway. Unicellular microorganisms spend most of their lifetime in harsh restricted environments interrupted by short windows of growth, making CLS an important and likely adaptive trait. I found that wild strains subjected to CLS tend to trigger the meiotic developmental process leading to the formation of gametes wrapped into a very resistant cell wall. In contrast, domesticated strains tend to enter quiescence state when starved and display a tremendous variability in their survival capacity. Moreover, using both candidate gene approach and genome-wide association studies (GWAS), I demonstrated that variability in CLS is determined by a full spectrum of genetic variant that include gene presence/absence, copy number variation, non-synonymous SNPs and loss of function. All these genetic features were strongly regulated by the environment. In the second part, I performed linkage analysis using 1056 diploid segregants derived from a two parent advanced intercross. These 1056 diploid segregants were phenotyped for CLS to map quantitative trait loci (QTLs). The CLS was measured in complete media, CR and RM environments across multiple time points. I mapped 30 distinct QTLs, with some shared across different environments and time points, while others were unique to a specific condition. The two major effect size QTLs were linked with natural variation in the cell wall glycoproteins FLO11 and HPF1, previously unknown to regulate CLS. Interestingly, both genes presented massive intragenic tandem repeat expansions in one of the founder strain used in the crossing scheme. While the short versions of FLO11 and HPF1 alleles did not impact CLS, tandem repeat expansions within those genes were sufficient to confer a dominant detrimental effect that was partially buffered by rapamycin treatment. Further investigation revealed that the extended form of HPF1 makes cells floating during exponential phase, exposing them to higher oxygen rates, and leading to perturbation of redox homeostasis, activation of misfolded protein response, and alteration of multiple genes involved in methionine, ribosome and lipid biosynthesis, eventually contributing to CLS shortening. Taken together, my work provided an unprecedented overview of natural variation in CLS in a genetic model system and revealed multiple genetic and environmental factors that shape the species phenotypic variation.
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Benjamin Barré. Natural variations in yeast aging reveal genetic and environmental factors. Cellular Biology. Université Côte d'Azur, 2018. English. ⟨NNT : 2018AZUR4237⟩. ⟨tel-02271640⟩

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