Experimental Evolution with Yeast Clifford Zeyl

MINIREVIEW Experimental evolution with yeast Clifford Zeyl

Department of Biology, Wake Forest University, Winston-Salem, NC, USA

Correspondence: Clifford Zeyl, Department Abstract of Biology, Wake Forest University, Winston- Downloaded from https://academic.oup.com/femsyr/article/6/5/685/563971 by guest on 27 September 2021 Salem NC 27109, USA. Tel.: 11 336 758-4292; Many of the difﬁculties of studying evolution in action can be surmounted using fax: 11 336 758-6008; populations of microorganisms, such as yeast. A readily manipulated sexual system e-mail: [email protected] and an increasingly sophisticated array of molecular and genomic tools uniquely qualify Saccharomyces cerevisiae as an experimental subject. This minireview Received 9 September 2005; revised 11 brieﬂy describes some recent contributions of yeast experiments to current November 2005; accepted 9 December 2005. understanding of the evolution of ploidy, sex, mutation, and speciation. First published online 21 March 2006. doi:10.1111/j.1567-1364.2006.00061.x

Editor: Teun Boekhout

Keywords experimental evolution; adaptation; recombination; ploidy; speciation.

recurrent emphasis in yeast experiments has been the Introduction evolution of the eukaryotic genetic system itself. Sex and Evolution is often thought of as being imperceptibly slow. A recombination, ploidy, and speciation are topics of espe- great deal of what we understand about evolution has cially broad evolutionary interest that have been the focus of therefore come from comparisons among existing species yeast experimental tests of theory. and from theoretical studies using modeling and simulation. A typical evolution experiment starts with microbiology But there are also increasingly frequent experimental tests of at its most basic: maintain axenic cultures for hundreds or evolutionary theory, performed on laboratory populations thousands of generations, periodically freezing samples of of organisms with generation times short enough that each population for analysis. Cultures are propagated either evolution can be observed directly, as it occurs. A pioneering by serial transfer (batch culture), in which a sample of each experiment that illustrates the potential scope of experi- population is transferred to a tube or plate of fresh medium mental microbial evolution is an ongoing study of 12 at regular intervals, or by chemostats, which balance inflow Escherichia coli populations through over 30 000 generations of fresh medium with outflow of used medium at constant in Richard Lenski’s laboratory (Table 1). From these popu- rates (Fig. 1). Chemostats are most often used to impose a lations have come rigorous tests of a great deal of evolu- constant selective environment, although periodic changes tionary theory. of medium can also be imposed, for example to induce In addition to short generation times, microbial evolu- meiosis and sporulation (Goddard et al., 2005). tion experiments have exploited the ease with which very The culture conditions define the type of selection to large populations can be maintained (allowing faster adap- which experimental populations will respond. They may tation), and the fact that samples of evolving populations include a specified type of stress, such as high osmolarity or can be frozen for later analysis and compared with their temperature (Goddard et al., 2005), or may simply place ancestor and with each other. Other experiments in evolu- populations in competition for a limiting nutrient such as tionary ecology and genetics have used Pseudomonas fluor- glucose. Whatever the selective pressure, rare mutations that escens (Rainey & Travisano, 1998) and the unicellular alga increase reproductive success will appear and increase in Chlamydomonas (Colegrave et al., 2002; Colegrave, 2002). frequency. Adaptation can then be measured either as a The current array of genetic and genomic technology makes simple growth rate or as competitive ability relative to a budding yeast ideally suited to experimental evolution. A reference genotype such as the ancestor of the experimental

Table 1. Some contributions of a long-term Escherichia coli evolution experiment Hypotheses and questions Main results Ref. The dynamics of fitness Rapid evolution for 2000 generations, then much slower change Lenski & Travisano (1994); Elena increase Replicate populations diverge in fitness et al. (1996) ‘‘Punctuated equilibrium:’’short periods of rapid change separated by periods of stasis, caused by the dynamics of selection of new mutations The roles of chance and history History and chance strongly affected cell size, which is correlated weakly with Travisano et al. (1995) in adaptation fitness, but not fitness itself The evolution and maintenance Two distinct, monophyletic ecotypes persisted for at least 14 000 generations, Rozen & Lenski (2000); Rozen of diversity fluctuating in frequencies, while both continued to adapt et al. (2005) The decay of metabolic functions Unused catabolic functions decayed due to antagonistic pleiotropy of Cooper & Lenski (2000)

that are released from selection adaptive mutations Downloaded from https://academic.oup.com/femsyr/article/6/5/685/563971 by guest on 27 September 2021 Mutation rates and effects Elevated mutation rates evolved in three adapting populations Elena & Lenski (1997); Harmful mutations do not generally interact synergistically, as required by Sniegowski et al. (1997) one hypothesis for the evolution of sex Molecular mechanisms of Changes in the expression of 59 genes evolved in parallel in two populations, Cooper et al. (2003) adaptation many of them regulated by cAMP populations. Competitive fitness is calculated from the per- produce homozygotes for that allele. In asexuals this can generation increase in frequency of the fitter genotype. In only occur in the unlikely event of the same mutation nature, it is rarely if ever possible to know the selective occurring again in the other allele (Kirkpatrick & Jenkins, environment in which a trait evolved, so the meaning of 1989). However, most hypotheses try to explain sex through fitness measurements may be uncertain. By contrast, experi- some advantage of randomizing allele combinations at mental evolution allows fitness estimates to be performed in separate loci. Recombining harmful mutations can increase exactly the same environment as that to which the experi- the variation in mutation load of the progeny. If mutation mental population adapted. Another tremendous advantage rates are high enough, and if mutations interact with each is the availability of genetic markers that do not affect other so as to aggravate their harmful effects, then sexual competitive fitness (Goldstein & McCusker, 1999). Cassettes progeny can have more than double the fitness of clones encoding resistance to G418, hygromycin, or nurseothricin (Kondrashov, 1988). Alternative hypotheses focus on adap- can be inserted at the HO locus of an ancestral genotype, tive mutations. Recombination can pair adaptive mutations where they are typically neutral, after that ancestor has been that have arisen in separate lineages. In an asexual popula- used to establish experimental populations. This allows the tion, no more than one adaptive mutation can be selected at competitive fitness of descendents to be quantified relative a time, and any other adaptive mutations present during to that of the ancestor. that interval are lost, a phenomenon known as clonal A simple yeast experiment will serve as an introduction to interference. Recombination can relieve clonal interference the basics of experimental evolution, and to one of the by allowing successive mutations to accumulate in one high- biggest puzzles remaining in evolutionary biology, the origin fitness genotype. Genetic and ecologic variations on this and maintenance of eukaryotic sex. idea are that recombination can separate an adaptive mutation from linked harmful mutations, or that the greater genetic diversity of a sexual brood of offspring reduces com- The evolution of sex petition among offspring compared to clones. Finally, accor- The puzzle is most clearly seen in organisms with distinct ding to the popular Red Queen hypothesis, it is antagonistic male and female gamete types, in which females provide co-evolution, such as that between parasites and their hosts, most or all of the resources needed by zygotes, but only half that constantly selects for rare or new allele combinations, as of the alleles they carry. Alleles encoding this behavior are each species adapts to counter the most successful and transmitted half as efficiently as female alleles for cloning. In abundant genotype of the other (Hamilton, 1980). the case of isogamous organisms such as yeast there is no A simple test for an advantage to recombining mutations such cost of sex because MATa and MATa gametes make used two environments: the rich medium YPD, which equal contributions in both alleles and resources, but mating contains abundant glucose and to which laboratory yeast consumes time that could otherwise be allocated to mitotic strains have already adapted, and the same medium with reproduction. Sex also imposes the risk of breaking up galactose substituted for glucose. Otherwise initially identi- successful combinations of alleles during recombination. It cal sexual and asexual populations were maintained on YPD has been suggested that the advantage of sex lies in the and YPGal for 400–600 generations. The ancestral strain for ability of heterozygotes for a new adaptive mutation to this experiment grew only about half as fast on galactose as

(a) Serial transfer. Samples of evolving populations preserved for analysis Inoculation of Inoculation of fresh medium fresh culture medium

Growth and reproduction Downloaded from https://academic.oup.com/femsyr/article/6/5/685/563971 by guest on 27 September 2021

(b) Chemostat.

Fresh medium

Spent medium, carrying samples of evolving population, (c) Competitive preserved for analysis fitness assay. Fig. 1. (a, b). Schematic comparisons of serial transfer and chemostat culture methods. (c) Estimation of competitive fitness. Relative Evolved sample and fitness is often calculated from the per- marked ancestor re- generation change in frequency of competi- acclimated to tors, as estimated from samples such as plated experimental environment and replica-plated colonies. DNA hybridization to arrays of oligonucleotides specific for parti- Mix competitors and Estimate frequencies estimate starting cular competitors can also be used to estimate after competition frequencies frequencies.

on glucose and was inefficient at inducing galactose meta- ing depression when inbred at the end of the experiment bolism (Menees & Sandmeyer, 1994), supporting the as- than did asexuals. sumption that the change in sugars would impose strong However, that experiment had a significant flaw: sexual selection for improved galactose catabolism. Significant but not asexual populations were periodically transferred to adaptation was observed, in the form of greatly increased sporulation medium (which imposes nitrogen starvation growth rates on galactose (Zeyl & Bell, 1997). However, and respiration of acetate) to induce meiosis, possibly asexuals adapted as well as sexuals did. An advantage for sex altering the selection experienced by sexuals. Other research was seen not on galactose but on the familiar YPD, where no has used populations established as mixtures of sexuals and significant increase in the growth rates of asexuals was seen. asexuals, forcing them to compete directly in the same The advantage of sex in a familiar environment was taken to serially transferred cultures, and using the fact that meiosis be the recombination of harmful mutations, making selec- is regulated by the mating type (MAT) locus. Diploids are tion against these mutations more efficient. In support of normally produced only by matings between haploids of this interpretation, sexual populations showed less inbreed- opposite mating types, MATa and MATa. Only MATa/MATa

random increasing numbers of adaptive mutation, so future tests of accumulation this hypothesis could manipulate population size and muta- of harmful tion rate. Sex should fare best in large populations and/or mutations with high mutation rates.

reduced Mutation, sex, and genetic parasites population fitness size declines The ease with which mutation rates can be manipulated genetically is another advantage of yeast for experimental evolution. The spontaneous mutation rate in yeast appears to be very low, on the order of 1 Â 10À4 per diploid cell

reduced Downloaded from https://academic.oup.com/femsyr/article/6/5/685/563971 by guest on 27 September 2021 reproductive division, at least in yeast with intact DNA repair systems. success Deletion of the mismatch repair gene MSH2 increases the rate of genome-wide mutation, affecting fitness by approxi- Fig. 2. Schematic illustration of the mutational meltdown hypothesis for extinction of small populations due to mutation accumulation. mately 100-fold (Zeyl & DeVisser, 2001), again offering the opportunity to test evolutionary theory using isogenic strains. A well-established effect of small or repeatedly diploids can undergo meiosis. Artificially engineered MATa/ bottlenecked population size is that, with random chance MATa and MATa/MATa diploids are incapable of meiosis, rivaling selection as a force determining which mutations and are at a competitive disadvantage (Birdsell & Wills, become common or fixed, fitness declines as slightly harm- 1996). But this does not necessarily indicate an advantage ful mutations accumulate. A more pessimistic family of for sex, because MAT heterozygotes were superior competi- models adds the assumption that, as relative fitness declines, tors even in the absence of meiotic recombination. At least reproductive rates decline and the ability of the population some of their advantage probably resulted from the wide- to maintain itself is eroded (Lynch & Gabriel, 1990; Gabriel spread regulatory effects that MAT heterozygosity has on et al., 1993). This sets up a positive-feedback loop in which gene expression in Saccharomyces cerevisiae (Herskowitz population size declines further, leading to further mutation et al., 1992; Durand et al., 1993). accumulation and further population decline (Fig. 2). The A more recent experiment exploited the propensity of implication is that a sufficiently high mutation rate could yeast cells for recombining similar DNA sequences, to drive a threatened population to extinction, even if its engineer asexual genotypes by surgically replacing one or habitat is maintained. However, it is not clear whether, in more genes with neutral marker flanked by target sequences. general, slightly harmful mutations occur frequently enough Deletion of SPO11 and SPO13 produces a genotype that to drive extinction, and times to extinction are greatly responds to the usual starvation triggers for meiosis and increased if population sizes are maintained by density sporulation by undergoing sporulation without a reduc- dependence and it is relative fitness, not absolute fitness, tional meiosis, producing two diploid spores. Otherwise that matters (Gabriel et al., 1993). identical sexual and asexual genotypes can therefore be used This ‘mutational meltdown’ hypothesis has been in more rigorous tests for an advantage of recombination. tested using wild-type and msh2 deletion mutant yeast Goddard et al. (2005) compared rates of adaptation over 300 (Zeyl et al., 2001). Because msh2 deletion increases muta- generations by sexual and asexual chemostat cultures in tion rates by two orders of magnitude, extinctions driven by both a standard glucose-limited medium and a harsh mutations were expected to occur more quickly and more medium with high osmolarity and a stressful temperature frequently in msh2D populations. Twelve populations of 37 1C. Adaptation was measured as fitness in competi- founded by each strain were maintained in 200-mL cultures tions between evolved and marked ancestral strains. On the transferred daily by a dilution factor that resulted in a standard medium there was no improvement and no geometric mean population size near 250. After about 2900 difference between sexuals and asexuals, but the sexuals asexual generations, the sizes of msh2D but not MSH2 adapted significantly more quickly to the harsh environ- populations were declining. Two extinctions occurred, both ment than the asexuals. msh2D populations, and by re-running the experiment with How to account for the contrast between these results and frozen samples, the sample by which extinction had become the lack of sexual advantage on galactose described above? inevitable was identified for one of the doomed populations. One possibility is that fewer mutations were selected for What about adaptation and beneficial mutations? Evolu- during galactose adaptation, providing fewer opportunities tionary geneticists often picture substitutions and small for sex to combine co-existing adaptive mutations. The insertions or deletions with small fitness effects adding up hypothesized advantage of recombination increases with to construct adaptive changes. However, the adaptive

c 2006 Federation of European Microbiological Societies FEMS Yeast Res 6 (2006) 685–691 Published by Blackwell Publishing Ltd. All rights reserved Experimental evolution with yeast 689 mutations tracked down in eight populations after 100–500 one of the far-reaching effects of sex: the risk of infection by generations in a glucose-limited chemostat were chromoso- genetic parasites. mal rearrangements resulting in particular aneuploidies and amplifications of chromosomal regions carrying hexose Ploidy transporters (Dunham et al., 2002). Why would the same The diploidy of most familiar plants and animals breeds an chromosomal breakpoints be repeatedly involved? The implicit assumption that diploidy is good. Surprisingly, breakpoints all occurred at the site of sequences related to there is no consensus on whether this is true, nor why. As one of the Ty retrotransposons. The locations of these with the evolution of sex, some obvious explanations leap elements evidently predispose that genome to produce those forward, but don’t stand up well to critical study. A diploid particular rearrangements. If chromosomal rearrangements is spared the cost of any recessive deleterious mutations, that alter copy number or expression of genes under selec- providing an immediate advantage if recessive mutations Downloaded from https://academic.oup.com/femsyr/article/6/5/685/563971 by guest on 27 September 2021 tion make up the most important mutations in adaptation occur often enough. Yeast mutation accumulation experi- to glucose limitation, then the failure of an msh2D mutator to ments (Korona, 1999) suggest tentatively that they do. adapt faster than the wild type is easily explained. Chromo- However, there is a long-term cost to tolerating harmful some rearrangements also figured prominently in two sepa- recessives: they accumulate. In the end, diploids are left with rate experiments in which S. cerevisiae evolved under limiting a greater load of mutations and lower fitness than haploids organic phosphate conditions (Hansche et al., 1978; Adams (Crow & Kimura, 1965). et al., 1992), and in wine fermentation strains (Querol et al., It has alternatively been suggested that the advantage of 2003), indicating that this is not an artifact of one experi- diploidy lies in heterozygosity, rather than diploidy itself, mental system. Nor is it unique to yeast: adaptive deletions of and the yeast MAT locus provides a classic example of the ribose operon involving transposition by IS150 elements heterozygote superiority (Birdsell & Wills, 1996). This has occurred within 2000 generations in all 12 E. coli populations not turned out to be true of yeast genes in general, and represented in Table 1 (Cooper et al., 2001). currently seems unlikely to be the main reason for diploidy. However, the evolutionary role of the yeast retrotranspo- As with sex, theories of ploidy evolution can focus on new sons is not straightforward. This is not the first indication adaptation instead of conserving existing traits. Diploids that Ty elements can cause adaptive mutations; Blanc & have the simple advantage of having twice the rate of adap- Adams (2003) observed two adaptive Ty1 insertions among tive mutation, a property that was invoked to explain the mutations selected over 1000 generations in chemostats. But greater adaptation shown by diploid than by haploid yeast in they also noted that a minority of Ty1 insertions were a chemostat experiment (Paquin & Adams, 1983). How- adaptive. The population-level benefit of the occasional ever, mutations in the heterozygous state are less efficiently adaptive mutation is an important effect of retrotranspo- selected for, to the extent that they are recessive. Whether sons, but not a satisfactory explanation for their original this cost outweighs the benefit is expected to depend on spread, given that their average fitness effect is negative. population size. In very large populations, adaptive muta- Instead, mobile genetic elements are thought to originate tions are continually produced even by haploids, which then and invade a population as genetic parasites, their spread have an advantage of responding faster to selection, while in made possible by sex. By dispersing themselves throughout a small populations it might be the adaptive mutation rate genome, retrotransposons increase the fraction of meiotic that limits the rate of adaptation (Orr & Otto, 1994). progeny that can inherit the elements. This meiotic cheating This reasoning was tested using otherwise identical can compensate for the genetic damage and fitness losses serially transferred haploid and diploid yeast populations of caused by retrotransposition and by recombination between contrasting sizes. Among large (about 13 million) popula- Ty sequences. tions, each grown in 10 mL liquid medium in test tubes, Here again, the ease with which the yeast life cycle and haploids were clearly faster to adapt to a glucose-limited genetic makeup can be manipulated make an experimental medium (Zeyl et al., 2003). When the experiment was test feasible. The hypothesis was that a Ty3 element would repeated with much smaller (14 000) populations, each in invade sexual but not asexual populations, as in the absence 200 mL medium, there was no difference. A well-supported, of sex there is no opportunity for a genetically harmful broadly applicable advantage to diploidy has yet to be element to infect new lineages. This is what was observed, identified, but this experiment confirms that population with a few complications (Zeyl et al., 1996). One complica- size is an important variable. tion was that particular transposed Ty3 elements became abundant in two of six populations, having either caused or Speciation hitch-hiked with adaptive mutations. This experiment served both to underline the importance of mobile elements Speciation is an evolutionary puzzle on a par with that of in the spectrum of spontaneous mutations, and to illustrate sex. Not much has been resolved about how speciation

FEMS Yeast Res 6 (2006) 685–691 c 2006 Federation of European Microbiological Societies Published by Blackwell Publishing Ltd. All rights reserved 690 C. Zeyl usually occurs, and there is definitely room for yeast experi- for which yeast experiments have yet to be reported, such as ments to contribute some valuable data. A few studies have the possibility of sympatric speciation through ecologic provided insights into the genetic mechanism by which specialization and the evolution of mate choice (Dieckmann species of Saccharomyces are kept genetically isolated. One & Doebeli, 1999). Finally, some aspects of yeast biology itself difficulty has been explaining how speciation can occur fast remain unexplained. For example, S. cerevisiae in nature is enough to prevent interbreeding from dissolving the emer- homothallic, leading to high levels of inbreeding that would ging genetic boundary, while leaving the new species self- seem to discard most of the hypothesized advantages of sex. fertile. Hybridization is one possible mechanism if newly Has the production of highly homozygous offspring been formed hybrids are sufficiently genetically isolated from selected for? Evolution experiments may prove to be the best both parental species, and if they are themselves capable of approach to this and other questions of yeast genetics. reproduction. 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