Structures of Naturally Evolved <i>CUP1</i> Tandem Arrays in Yeast Indicate That These Arrays Are Generated by Unequal Nonhomologous Recombination

Zhao, Ying; Strope, Pooja K; Kozmin, Stanislav G.; McCusker, John H.; Dietrich, Fred S.; Kokoska, Robert J.; Petes, Thomas D.

doi:10.1534/g3.114.012922

Cited by 49 publications

(67 citation statements)

References 39 publications

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“…Relative to the three control genes, the BMN lines had an average of 18.13 copies of CUP1 (range: 12.40-30.45). Note that although the S288C reference genome on the SGD reports only two CUP1 copies, an isolate of S288C was recently found to contain $14 copies by Southern analysis (Zhao et al 2014). Our data are thus consistent with our ancestral BY4741 strain having undergone amplification in this region, and we report the number of CUP1 copies in our copper adaptation strains relative to the average across the BMN lines.…”

supporting

confidence: 86%

“…Indeed, Covo et al (2014) recently demonstrated that moving CUP1 onto other chromosomes can efficiently select for disomy under copper stress. The number of CUP1 copies varies among naturally isolated wild and vineyard strains (between 1 and 18 copies among 14 wild strains, Zhao et al 2014, and 4 and 18 copies among 15 Italian vineyard strains, Stroobants et al 2008). As CUP1 is present in the ancestral genome as a tandem repeat, it is likely prone to alterations in copy number as a consequence of unequal crossover, gene conversion, or single-strand annealing (Zhang et al 2013).…”

Section: Discussionmentioning

confidence: 99%

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Too Much of a Good Thing: The Unique and Repeated Paths Toward Copper Adaptation

Gerstein

Ono

et al. 2014

Genetics

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Copper is a micronutrient essential for growth due to its role as a cofactor in enzymes involved in respiration, defense against oxidative damage, and iron uptake. Yet too much of a good thing can be lethal, and yeast cells typically do not have tolerance to copper levels much beyond the concentration in their ancestral environment. Here, we report a short-term evolutionary study of Saccharomyces cerevisiae exposed to levels of copper sulfate that are inhibitory to the initial strain. We isolated and identified adaptive mutations soon after they arose, reducing the number of neutral mutations, to determine the first genetic steps that yeast take when adapting to copper. We analyzed 34 such strains through whole-genome sequencing and by assaying fitness within different environments; we also isolated a subset of mutations through tetrad analysis of four lines. We identified a multilayered evolutionary response. In total, 57 single base-pair mutations were identified across the 34 lines. In addition, gene amplification of the copper metallothionein protein, CUP1-1, was rampant, as was chromosomal aneuploidy. Four other genes received multiple, independent mutations in different lines (the vacuolar transporter genes VTC1 and VTC4; the plasma membrane H+-ATPase PMA1; and MAM3, a protein required for normal mitochondrial morphology). Analyses indicated that mutations in all four genes, as well as CUP1-1 copy number, contributed significantly to explaining variation in copper tolerance. Our study thus finds that evolution takes both common and less trodden pathways toward evolving tolerance to an essential, but highly toxic, micronutrient.KEYWORDS Saccharomyces cerevisiae; genetic basis of adaptation; copper tolerance; aneuploidy; CUP1; fitness; parallel adaptation I N his book, Wonderful Life (Gould 1989, p. 51), Stephen J. Gould famously opined that evolution is a historical and contingent process, so much so that "any replay of the tape would lead evolution down a pathway radically different from the road actually taken." While this is undoubtedly true when one considers the full complexity of an organism, refrains are often observed in evolution at the trait level. Repeated evolution, defined as "the independent appearance of similar phenotypic traits in distinct evolutionary lineages" (Gompel and Prud'homme 2009) has been documented in both ecological and clinical environments at all taxonomic levels, e.g., repeated loss of stickleback lateral plates in freshwater (Schluter et al. 2004), ecomorphs of Anolis lizards (Losos 1992), the acquisition of "cystic fibrosis lung" phenotypes in Pseudomonas aeruginosa in patients with cystic fibrosis (Huse et al. 2010), to name but a few. The development of sequencing technologies has recently allowed biologists to ask whether parallel genetic changes underlie observations of parallel phenotypic change. In some cases, parallel phenotypic evolution has been attributed to parallel genotypic evolution, for example, repeated changes to cis-regulatory regions of the same...

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supporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Too Much of a Good Thing: The Unique and Repeated Paths Toward Copper Adaptation

Gerstein

Ono

et al. 2014

Genetics

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“…2; Supplemental Tables S5, S14). Similarly, CUP1 copy number has been precisely determined in very few strains (Fogel and Welch 1982;Hamer et al 1985;Zhao et al 2014). Based on CUP1 sequence coverage relative to flanking single-copy sequences, CUP1 copy number in the 93 strains varied from one copy (28 strains) to 18 copies (Supplemental Table S15).…”

Section: Genome Sequence Data Defines Multiple Types Of Genetic Variamentioning

confidence: 99%

The 100-genomes strains, an S. cerevisiae resource that illuminates its natural phenotypic and genotypic variation and emergence as an opportunistic pathogen

et al. 2015

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Saccharomyces cerevisiae, a well-established model for species as diverse as humans and pathogenic fungi, is more recently a model for population and quantitative genetics. S. cerevisiae is found in multiple environments-one of which is the human body-as an opportunistic pathogen. To aid in the understanding of the S. cerevisiae population and quantitative genetics, as well as its emergence as an opportunistic pathogen, we sequenced, de novo assembled, and extensively manually edited and annotated the genomes of 93 S. cerevisiae strains from multiple geographic and environmental origins, including many clinical origin strains. These 93 S. cerevisiae strains, the genomes of which are near-reference quality, together with seven previously sequenced strains, constitute a novel genetic resource, the "100-genomes" strains. Our sequencing coverage, highquality assemblies, and annotation provide unprecedented opportunities for detailed interrogation of complex genomic loci, examples of which we demonstrate. We found most phenotypic variation to be quantitative and identified population, genotype, and phenotype associations. Importantly, we identified clinical origin associations. For example, we found that an introgressed PDR5 was present exclusively in clinical origin mosaic group strains; that the mosaic group was significantly enriched for clinical origin strains; and that clinical origin strains were much more copper resistant, suggesting that copper resistance contributes to fitness in the human host. The 100-genomes strains are a novel, multipurpose resource to advance the study of S. cerevisiae population genetics, quantitative genetics, and the emergence of an opportunistic pathogen.

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“…In a survey of 100 different S. cerevisiae strains, about twothirds have tandem arrays of CUP1 repeats (21,22). Strain DZ12 has about 16 copies of CUP1, with 12 copies on the W303-1A-derived homolog and 4 on the YJM789 homolog (Fig.…”

Section: Association Of Loh Events With Elements Of Chromosome Sequenmentioning

confidence: 99%

Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae

Zheng

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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DNA replication stress (DRS)-induced genomic instability is an important factor driving cancer development. To understand the mechanisms of DRS-associated genomic instability, we measured the rates of genomic alterations throughout the genome in a yeast strain with lowered expression of the replicative DNA polymerase δ. By a genetic test, we showed that most recombinogenic DNA lesions were introduced during S or G 2 phase, presumably as a consequence of broken replication forks. We observed a high rate of chromosome loss, likely reflecting a reduced capacity of the lowpolymerase strains to repair double-stranded DNA breaks (DSBs). We also observed a high frequency of deletion events within tandemly repeated genes such as the ribosomal RNA genes. By whole-genome sequencing, we found that low levels of DNA polymerase δ elevated mutation rates, both single-base mutations and small insertions/ deletions. Finally, we showed that cells with low levels of DNA polymerase δ tended to accumulate small promoter mutations that increased the expression of this polymerase. These deletions conferred a selective growth advantage to cells, demonstrating that DRS can be one factor driving phenotypic evolution.DNA replication stress | DNA polymerase | genome instability I n normal rapidly dividing cells, DNA replication is rapid and accurate, preventing the accumulation of genomic alterations. Stalling of replication forks or inappropriate initiation of replication origins can result in DNA replication stress (DRS) that can contribute to cancer development (1). It has been proposed that mutations in oncogenes and tumor suppressor genes drive cell proliferation and induce DRS. In turn, DRS generates genome instability, allowing cells with various types of genetic variations (mutations, duplications, translocations) to escape cellular senescence and apoptosis (2). However, the mechanisms by which oncogenes induce DRS and the precise nature of DRSassociated DNA lesions have not been clearly defined.Exposure of mammalian cells in culture to conditions that perturb DNA synthesis result in "fragile sites," gaps or constrictions detected by light microscopy in metaphase chromosomes (3). Aphidicolin, a drug that inhibits DNA polymerase, is one agent that induces fragile sites. The break points of chromosome rearrangements that occur in tumor cells often colocalize with fragile sites (3, 4), establishing another link between DRS and cancer. In addition to inducing chromosome breaks in cultured cells, aphidicolin induces high frequencies of duplications and deletions similar to those observed in tumor cells (5).As a model for mammalian fragile sites, we previously constructed yeast strains in which the transcription of the replicative DNA polymerases α (encoded by POL1) or δ (encoded by POL3) was regulated by the GAL1 promoter (6-8). Under lowgalactose growth conditions, which reduced the levels of DNA polymerases α or δ about 10-fold, these strains had elevated rates of chromosome loss and rearrangements on chromosome III.We also studied g...

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Structures of Naturally Evolved CUP1 Tandem Arrays in Yeast Indicate That These Arrays Are Generated by Unequal Nonhomologous Recombination

Cited by 49 publications

References 39 publications

Too Much of a Good Thing: The Unique and Repeated Paths Toward Copper Adaptation

Too Much of a Good Thing: The Unique and Repeated Paths Toward Copper Adaptation

The 100-genomes strains, an S. cerevisiae resource that illuminates its natural phenotypic and genotypic variation and emergence as an opportunistic pathogen

Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae

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