Revisiting the Budding Yeast Life Cycle – BuddY

Saccharomyces cerevisiae has served as a model for nearly a century to understand the principles of the eukaryotic life cycle. The classical budding yeast life cycle describes an alternation between diploid and haploid phases. Diploid cells proliferate mitotically under nutrient rich conditions and undergo meiosis when encountering nutrient limitation to produce tetrads composed of four haploid spores. Upon germination, spores from opposite mating types mate to restore diploids. Alternatively, haploid mother cells can change their mating type by a programmed switching mechanism allowing them to mate with their daughters to re-establish the diploid state by haploselfing. Various studies have shown that inbreeding through inter-spore mating or haploselfing would largely exceed outcrossing events by inter-tetrad mating between different lineages. Both inbreeding and haploselfing promote a rapid loss of heterozygosity and therefore most natural isolates are expected to be homozygous diploids.

Contrary to this expectation, a large-scale population genomic survey in Saccharomyces cerevisiae recently unveiled the quantitative importance of heterozygous and polyploid isolates in both domesticated and wild populations. Such genomic makeup suggests an unanticipated complexity of the yeast life cycle. How heterozygosity and polyploidy are generated and maintained in the population remains a mystery. In addition, the population genomic data revealed a striking association between heterozygosity and polyploidy, with all triploid and tetraploid isolates being highly heterozygous. The relationship between polyploidy formation and heterozygosity is equally unknown. In this proposal, we hypothesize that alternative routes may shape the natural yeast life cycle. We suggest that multiple mechanisms such as unprogrammed mating type switching, heterothallism, reduced spore formation and viability, cell-cell fusion and dioecy could play key and uncharted contributions to generate and maintain heterozygosity through polyploidization.

More precisely, we aim to understand the mechanisms and evolutionary forces that underlie the generation and maintenance of highly heterozygous and polyploid isolates, and their consequences on genome evolution through three interconnected objectives combining bioinformatics, genome editing, experimental evolution and mathematical modelling. We will reconstruct the admixture events that shaped the species evolutionary history and engineer a strain library to experimentally investigate mechanisms that could lead to new life cycle routes. We will measure the impact of such genomic complexity on the mutational and recombination landscapes of the organism and use mathematical modelling to test specific scenarios that recapitulate population genomics data into an explicative evolutionary framework. This work will shed new light on the real complexity of the yeast life cycle. It may lead to the discovery of alternative sexual strategies with important consequences on the genetic makeup of the species and potential repercussions on the domestication process. Overall, our work may prime similar fundamental studies reconsidering the complexity of the life cycle in other species. The improved ability to control the yeast life cycle resulting from our project might offer novel and non-GMO avenues to manipulate industrial yeast strains for improved biotechnological applications.