Loss-of-heterozygosity facilitates passage through Haldane’s sieve for Saccharomyces cerevisiae undergoing adaptation

Gerstein, Aleeza C.; Kuzmin, Anastasia; Otto, Sarah P.

doi:10.1038/ncomms4819

Cited by 62 publications

(57 citation statements)

References 32 publications

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“…Considering the various diploid heterozygotes, we confirmed that the ergosterol mutations were largely recessive, as found previously for the single heterozygous mutant strains [33]. There were more signs of nystatin resistance in the double mutant strains than in the single mutants, however.…”

Section: Discussionsupporting

confidence: 88%

“…This may have occurred during the course of the fitness assay, affecting our final measures of fitness. LOH was previously observed for the single heterozygous mutants over a 72-hour timescale [33], and being heterozygous for two mutations may increase the chance of LOH for at least one of the two. The unexpected increase in fitness in the double heterozygotes may also be indicative of an epistatic interaction providing some benefit to having two heterozygous mutations within the ergosterol pathway compared to full recessivity (i.e., no benefit) with only a single heterozygous mutation [33].…”

Section: Resultsmentioning

confidence: 99%

“…OD was measured automatically using the wideband filter at 30-min intervals for 24 hours from cultures growing at 30°C with maximum continuous shaking. Longer assays were avoided because mutations and LOH events began to accumulate [33]. The maximum growth rate over 24 hours was determined by the spline with the highest slope from a loess fit through natural log transformed OD data, using a custom script written by Richard FitzJohn in R [57] (see Dryad for code [32]).…”

Section: Methodsmentioning

confidence: 99%

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Widespread Genetic Incompatibilities between First-Step Mutations during Parallel Adaptation of Saccharomyces cerevisiae to a Common Environment

2017

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Independently evolving populations may adapt to similar selection pressures via different genetic changes. The interactions between such changes, such as in a hybrid individual, can inform us about what course adaptation may follow and allow us to determine whether gene flow would be facilitated or hampered following secondary contact. We used Saccharomyces cerevisiae to measure the genetic interactions between first-step mutations that independently evolved in the same biosynthetic pathway following exposure to the fungicide nystatin. We found that genetic interactions are prevalent and predominantly negative, with the majority of mutations causing lower growth when combined in a double mutant than when alone as a single mutant (sign epistasis). The prevalence of sign epistasis is surprising given the small number of mutations tested and runs counter to expectations for mutations arising in a single biosynthetic pathway in the face of a simple selective pressure. Furthermore, in one third of pairwise interactions, the double mutant grew less well than either single mutant (reciprocal sign epistasis). The observation of reciprocal sign epistasis among these first adaptive mutations arising in the same genetic background indicates that partial postzygotic reproductive isolation could evolve rapidly between populations under similar selective pressures, even with only a single genetic change in each. The nature of the epistatic relationships was sensitive, however, to the level of drug stress in the assay conditions, as many double mutants became fitter than the single mutants at higher concentrations of nystatin. We discuss the implications of these results both for our understanding of epistatic interactions among beneficial mutations in the same biochemical pathway and for speciation.

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Widespread Genetic Incompatibilities between First-Step Mutations during Parallel Adaptation of Saccharomyces cerevisiae to a Common Environment

2017

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“…However, depending on the environmental challenge, this may [26], or may not [19], be the case. An increase in ploidy also increases the mutation rate [19], and, if selection is strong, loss of heterozygosity can rapidly convert heterozygous mutations to a homozygous state [27], thereby reducing the difference in the rate of adaptation between haploids (where the effect of recessive beneficial mutations are immediately felt) and higher ploidy levels. Finally, mutations may also have different effect sizes in different ploidy backgrounds, even when present in homozygous form [28].…”

Section: Does Ploidy State Provide a Selective Advantage?mentioning

confidence: 99%

Shift and adapt: the costs and benefits of karyotype variations

Gerstein

Berman

2015

Current Opinion in Microbiology

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Variation is the spice of life or, in the case of evolution, variation is the necessary material on which selection can act to enable adaptation. Karyotypic variation in ploidy (the number of homologous chromosome sets) and aneuploidy (imbalance in the number of chromosomes) are fundamentally different than other types of genomic variants. Karyotypic variation emerges through different molecular mechanisms than other mutational events, and unlike mutations that alter the genome at the base pair level, rapid reversion to the wild type chromosome number is often possible. Although karyotypic variation has long been noted and discussed by biologists, interest in the importance of karyotypic variants in evolutionary processes has spiked in recent years, and much remains to be discovered about how karyotypic variants are produced and subsequently selected.

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“…However, this study focused on fungicide resistance (a component of fitness) rather than on the overall fitness, and thus it may have failed to detect fitness overdominance for some of the resistant mutations by overlooking increased pleiotropic costs of the homozygous resistant mutations. Similarly, Gerstein et al (2014) found limited evidence for fitness overdominance in resistance to nystatin in adapting yeast populations. However, these studies potentially miss adaptive mutations unique to diploids by assuming that they acquire beneficial mutations in the same genes as haploids when adapting to the same environmental stress.…”

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confidence: 99%

Heterozygote Advantage Is a Common Outcome of Adaptation inSaccharomyces cerevisiae

et al. 2016

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Adaptation in diploids is predicted to proceed via mutations that are at least partially dominant in fitness. Recently, we argued that many adaptive mutations might also be commonly overdominant in fitness. Natural (directional) selection acting on overdominant mutations should drive them into the population but then, instead of bringing them to fixation, should maintain them as balanced polymorphisms via heterozygote advantage. If true, this would make adaptive evolution in sexual diploids differ drastically from that of haploids. The validity of this prediction has not yet been tested experimentally. Here, we performed four replicate evolutionary experiments with diploid yeast populations (Saccharomyces cerevisiae) growing in glucose-limited continuous cultures. We sequenced 24 evolved clones and identified initial adaptive mutations in all four chemostats. The first adaptive mutations in all four chemostats were three copy number variations, all of which proved to be overdominant in fitness. The fact that fitness overdominant mutations were always the first step in independent adaptive walks supports the prediction that heterozygote advantage can arise as a common outcome of directional selection in diploids and demonstrates that overdominance of de novo adaptive mutations in diploids is not rare.KEYWORDS heterozygote advantage; experimental evolution; adaptation; diploid T HE most immediate difference between diploids and haploids is that diploids have twice as many gene copies and thus roughly twice as many expected mutations per individual per generation, assuming the same mutation rate per nucleotide. If adaptation is limited by the waiting time for new adaptive mutations, this suggests that diploids might enjoy an adaptive advantage over haploids; indeed, it has been argued that the rate of adaptive evolution in diploids might be double that in haploids (Paquin and Adams 1983;Anderson et al. 2004) [although see Zeyl et al. (2003) and Gerstein et al. (2011)].Diploids, however, might also suffer an adaptive disadvantage. New mutations in diploids are heterozygous, and their effect is thus "diluted" or even completely masked by the presence of the ancestral allele. Unless mutations are fully dominant in fitness, this reduces the probability of fixation of new beneficial mutations and increases the expected frequency that can be reached by deleterious mutations. This fitness effect "dilution" also slows down fixation of adaptive alleles in diploids by roughly twofold when adaptive mutations are codominant in fitness, and by more than that when adaptive mutations are either recessive (they spread in the population slowly) or fully dominant (they suffer a slowdown at high frequencies). This suggests that haploids should gain an advantage in adapting to new environments when the rate of spread of adaptive mutations is the limiting step in adaptation.These considerations have underpinned a large body of theory (Otto and Gerstein 2008) and generated some specific predictions. One of these is known as Hal...

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Loss-of-heterozygosity facilitates passage through Haldane’s sieve for Saccharomyces cerevisiae undergoing adaptation

Cited by 62 publications

References 32 publications

Widespread Genetic Incompatibilities between First-Step Mutations during Parallel Adaptation of Saccharomyces cerevisiae to a Common Environment

Widespread Genetic Incompatibilities between First-Step Mutations during Parallel Adaptation of Saccharomyces cerevisiae to a Common Environment

Shift and adapt: the costs and benefits of karyotype variations

Heterozygote Advantage Is a Common Outcome of Adaptation inSaccharomyces cerevisiae

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