Mating-Type Switching in Budding Yeasts, from Flip/Flop Inversion to Cassette Mechanisms

Abstract

Mating-type switching is a natural but unusual genetic control process that regulates cell identity in ascomycete yeasts. It involves physically replacing one small piece of genomic DNA by another, resulting in replacement of the master regulatory genes in the mating pathway and hence a switch of cell type and mating behavior. In this review, we concentrate on recent progress that has been made on understanding the origins and evolution of mating-type switching systems in budding yeasts (subphylum Saccharomycotina). Because of the unusual nature and the complexity of the mechanism in Saccharomyces cerevisiae, mating-type switching was assumed until recently to have originated only once or twice during yeast evolution. However, comparative genomics analysis now shows that switching mechanisms arose many times independently-at least 11 times in budding yeasts and once in fission yeasts-a dramatic example of convergent evolution. Most of these lineages switch mating types by a flip/flop mechanism that inverts a section of a chromosome and is simpler than the well-characterized 3-locus cassette mechanism (MAT/HML/HMR) used by S. cerevisiae. Mating-type switching (secondary homothallism) is one of the two possible mechanisms by which a yeast species can become self-fertile. The other mechanism (primary homothallism) has also emerged independently in multiple evolutionary lineages of budding yeasts, indicating that homothallism has been favored strongly by natural selection. Recent work shows that HO endonuclease, which makes the double-strand DNA break that initiates switching at the S. cerevisiae MAT locus, evolved from an unusual mobile genetic element that originally targeted a glycolytic gene, FBA1.

Keywords: homothallism; mating type; yeast.

FIG 1

Role of mating-type switching in the life cycle of S. cerevisiae.

FIG 2

Functions of the four canonical MAT genes in a typical budding yeast species. In haploids, the a2 and α1 proteins activate the mating programs specific to each cell type. In diploids, the a1/α2 heterodimer represses these programs.

FIG 3

Organization of the MAT loci in three budding yeast species. Hatched lines indicate regions that are transcriptionally silenced. CEN and TEL indicate centromeres and telomeres, respectively. Asterisks in gene names indicate truncated duplicated genes located in the repeat regions. (A) Ogataea polymorpha, a species with a flip/flop system involving one IR (FF1). The regions highlighted in blue form the IR. In the orientation shown, only the MATa genes are expressed. (B) Komagataella phaffii, a species with a flip/flop system involving two IRs (FF2). The regions highlighted in blue form the outer IR, and the regions highlighted in purple form the inner IR. In the orientation shown, only the MATα genes are expressed. (C) Saccharomyces cerevisiae, a species with a 3-locus cassette system. The three identical X regions are highlighted in blue, and the three identical Z regions are highlighted in purple; they form direct repeats on S. cerevisiae chromosome III. In the arrangement shown, only the MATα genes are expressed.

FIG 4

Evolutionary transitions between different mating systems in 332 budding yeast species (modified from reference 26). The three gray boxes show MAT locus arrangements consistent with heterothallism (center), primary homothallism (left), or secondary homothallism (right). Within secondary homothallism, species were classified into three groups (FF1, FF2, or 3LOC) depending on the arrangements of repeat sequences (shown in blue and purple) flanking the MAT genes. Within primary homothallism, species were classified into two groups (PHC and PHN) depending on whether the MATa and MATα genes in a genome were contiguous or not. Arrows show the inferred numbers of evolutionary transitions between systems (Fig. 5); black arrows mark transitions from heterothallism to homothallism. Modified from reference (with reassignment of Candida sojae from NOMAT to HET) published under the terms of the Creative Commons Attribution License (CC BY 4.0).

FIG 5

Transitions to homothallism on the phylogenomic tree of Saccharomycotina. Thickened branches represent homothallic species, colored as in the key. Thin branches represent heterothallic species. The tree topology and clade labels are from Shen et al. (25). Genera in which transitions to homothallism occurred are named. (This does not necessarily mean that all species in the genus are homothallic.) Modified from reference published under the terms of the Creative Commons Attribution License (CC BY 4.0).

FIG 6

Recent transition from heterothallism to flip/flop mating-type switching (secondary homothallism) within the genus Cyberlindnera. The tree shows an expanded view of part of Fig. 5. Blue branches indicate species inferred to switch mating types by an FF1 mechanism, and black branches indicate species inferred to be heterothallic, based on their genome sequences (26). The cartoons show gene organization around the MAT loci in two species. C. jadinii is inferred to be heterothallic diploid, with allelic MATα and MATa loci on different contigs in the genome assembly. C. saturnus has MATα genes at a position syntenic with the C. jadinii MAT locus and MATa genes 49 kb away on the same contig. The two sets of C. saturnus MAT genes are flanked by an IR, so it is inferred to switch mating types by an FF1 mechanism similar to Ogataea polymorpha. Modified from reference published under the terms of the Creative Commons Attribution License (CC BY 4.0).

FIG 7

Schematic phylogeny of budding yeast genera, showing the inferred points of origin of the 3-locus MAT/HML/HMR cassette system (3LOC), HO endonuclease, WHO endonucleases, α3, and KAT1 genes. Ψ symbols indicate WHO pseudogenes, and numbers of plus symbols indicate abundance. Most of the species shown are in family Saccharomycetaceae; Hanseniaspora, Wickerhamomyces, and Candida albicans are outgroups from other families.

FIG 8

Organization of WHO genes and pseudogenes and FBA1 fragments downstream of the full-length FBA1 gene in Torulaspora and related species. Six different alleles are shown for T. delbrueckii, three for T. pretoriensis, and two for T. globosa. Numbers indicate different families of WHO genes. Reproduced from reference published under the terms of the Creative Commons Attribution License.

FIG 9

Similarity of (A) the proposed mechanism of WHO element homing into the FBA1 locus, (B) the known mechanism of VDE intein homing into the VMA1 locus, and (C) the known mechanism of mating-type switching in S. cerevisiae. R and S indicate alleles resistant or sensitive to cleavage by endonuclease, respectively. Green shading of the 3′ end of FBA1 indicates sequence variants resistant to cleavage by this WHO endonuclease. Modified from reference published under the terms of the Creative Commons Attribution License.

FIG 10

The “resporulation” hypothesis postulates that homothallism enables spores to germinate early without risking extinction. The black curves represent two scenarios: one in which the environment improves continuously over time (A) and one in which the environment fluctuates over time (B and C). The cartoons show two spores (red and blue) germinating and expanding clonally as environmental conditions improve. Circles represent spores, and ovals represent vegetative cells. Spore 1 (red) has a lower threshold for the quality of environment required for germination than spore 2 (blue). (A) If the environment improves smoothly, spore 1 leaves more descendants than spore 2 because it germinates earlier. (B) If the environment fluctuates and returns to conditions in which vegetative cells cannot survive, spore 1 germinates too early. If it is heterothallic and cannot find a mating partner, it will leave no descendants and go extinct. (C) In the same fluctuating environment, if spore 1’s haploid descendants are homothallic and able to mate with each other, the lineage can resporulate and survive the uninhabitable period. When the environment improves again, the spore 1 lineage will germinate earlier and outnumber the spore 2 lineage.