{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T17:13:43Z","timestamp":1778087623962,"version":"3.51.4"},"reference-count":49,"publisher":"The Royal Society","issue":"5","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of General Medical Sciences of the National Institutes of Health"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Genomic regions containing tandem duplications may be subject to particularly high rates of copy number mutations due to recombinational repair of DNA damage. Consequently, changes in copy number may be among the most accessible beneficial mutations during evolution in a new environment. In the budding yeast Saccharomyces cerevisiae, the gene CUP1 occurs in multiple tandem copies and encodes a metallothionein relevant for copper homeostasis. We examined CUP1 copy number in 220 mutation accumulation lines and their ancestors to quantify spontaneous genetic change at this locus. We also measured copper tolerance in these strains to understand the phenotypic effects of CUP1 copy number change and other mutations. Mutations in CUP1 copy number occurred relatively rapidly, with a bias towards losses. While copper tolerance also declined due to mutations, this change was less rapid and was only partly driven by CUP1 copy number. Thus, while CUP1 is highly susceptible to copy number change, our results add to a body of evidence that these accessible mutations on their own do not fully account for variation in copper tolerance.<\/jats:p>","DOI":"10.1098\/rsbl.2026.0090","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T04:40:02Z","timestamp":1778042402000},"source":"Crossref","is-referenced-by-count":0,"title":["The effect of spontaneous mutations on\n                    <i>CUP1<\/i>\n                    copy number and copper tolerance in\n                    <i>Saccharomyces cerevisiae<\/i>"],"prefix":"10.1098","volume":"22","author":[{"given":"Rohan","family":"Sohoni","sequence":"first","affiliation":[{"name":"University of Wisconsin-Madison 1 , , ,","place":["Madison, WI, USA"],"department":["Department of Genetics"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gillian G.","family":"Schatz","sequence":"additional","affiliation":[{"name":"University of Wisconsin-Madison 1 , , ,","place":["Madison, WI, USA"],"department":["Department of Genetics"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6016-083X","authenticated-orcid":false,"given":"Nathaniel","family":"Sharp","sequence":"additional","affiliation":[{"name":"University of Wisconsin-Madison 1 , , ,","place":["Madison, WI, USA"],"department":["Department of Genetics"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"2026050612440116100_R1","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-642-86659-3","volume-title":"Evolution by gene duplication","author":"Ohno","year":"1970"},{"key":"2026050612440116100_R2","doi-asserted-by":"crossref","DOI":"10.3389\/fgene.2013.00273","article-title":"Copy-number changes in evolution: rates, fitness effects and adaptive significance","volume":"4","author":"Katju","year":"2013","journal-title":"Front. Genet."},{"key":"2026050612440116100_R3","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrg2593","article-title":"Mechanisms of change in gene copy number","volume":"10","author":"Hastings","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"2026050612440116100_R4","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1146\/annurev.mi.31.100177.002353","article-title":"Tandem genetic duplications in phage and bacteria","volume":"31","author":"Anderson","year":"1977","journal-title":"Annu. Rev. Microbiol."},{"key":"2026050612440116100_R5","doi-asserted-by":"crossref","DOI":"10.1186\/gb-2007-8-8-r158","article-title":"Quantifying the major mechanisms of recent gene duplications in the human and mouse genomes: a novel strategy to estimate gene duplication rates","volume":"8","author":"Pan","year":"2007","journal-title":"Genome Biol."},{"key":"2026050612440116100_R6","doi-asserted-by":"crossref","first-page":"2259","DOI":"10.1534\/g3.114.012922","article-title":"Structures of naturally evolved CUP1 tandem arrays in yeast indicate that these arrays are generated by unequal nonhomologous recombination","volume":"4","author":"Zhao","year":"2014","journal-title":"G3 Genes Genomes Genet."},{"key":"2026050612440116100_R7","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s00294-002-0346-3","article-title":"Mitotic recombination in Saccharomyces cerevisiae","volume":"42","author":"Prado","year":"2003","journal-title":"Curr. Genet."},{"key":"2026050612440116100_R8","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1146\/annurev.ecolsys.39.110707.173437","article-title":"Spontaneous mutation accumulation studies in evolutionary genetics","volume":"40","author":"Halligan","year":"2009","journal-title":"Annu. Rev. Ecol. Evol. Syst."},{"key":"2026050612440116100_R9","article-title":"Old trade, new tricks: insights into the spontaneous mutation process from the partnering of classical mutation accumulation experiments with high-throughput genomic approaches","volume":"11","author":"Katju","year":"2018","journal-title":"Genome Biol. Evol."},{"key":"2026050612440116100_R10","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1534\/genetics.113.151670","article-title":"Rates and genomic consequences of spontaneous mutational events in Drosophila melanogaster","volume":"194","author":"Schrider","year":"2013","journal-title":"Genetics"},{"key":"2026050612440116100_R11","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1101\/gr.191338.115","article-title":"High mutational rates of large-scale duplication and deletion in Daphnia pulex","volume":"26","author":"Keith","year":"2016","journal-title":"Genome Res."},{"key":"2026050612440116100_R12","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.1801930115","article-title":"Mutational and transcriptional landscape of spontaneous gene duplications and deletions in Caenorhabditis elegans","volume":"115","author":"Konrad","year":"2018","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026050612440116100_R13","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1101\/gr.234724.118","article-title":"Accelerated rates of large-scale mutations in the presence of copper and nickel","volume":"29","author":"Chain","year":"2018","journal-title":"Genome Res."},{"key":"2026050612440116100_R14","doi-asserted-by":"crossref","DOI":"10.1093\/gbe\/evad179","article-title":"Contribution of spontaneous mutations to quantitative and molecular variation at the highly repetitive rDNA locus in yeast","volume":"15","author":"Sharp","year":"2023","journal-title":"Genome Biol. Evol."},{"key":"2026050612440116100_R15","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1007\/s00239-022-10081-1","article-title":"Very low rates of spontaneous gene deletions and gene duplications in Dictyostelium discoideum","volume":"91","author":"Gill","year":"2023","journal-title":"J. Mol. Evol."},{"key":"2026050612440116100_R16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41586-025-09637-0","article-title":"From genotype to phenotype with 1,086 near telomere-to-telomere yeast genomes","volume":"648","author":"Loegler","year":"2025","journal-title":"Nature"},{"key":"2026050612440116100_R17","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1002111","article-title":"Trait variation in yeast is defined by population history","volume":"7","author":"Warringer","year":"2011","journal-title":"PLoS Genet."},{"key":"2026050612440116100_R18","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1534\/g3.117.040105","article-title":"Extensive copy number variation in fermentation-related genes among Saccharomyces cerevisiae wine strains","volume":"7","author":"Steenwyk","year":"2017","journal-title":"G3"},{"key":"2026050612440116100_R19","doi-asserted-by":"crossref","first-page":"3332","DOI":"10.1073\/pnas.81.11.3332","article-title":"Copper metallothionein of yeast, structure of the gene, and regulation of expression","volume":"81","author":"Butt","year":"1984","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026050612440116100_R20","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1007\/BF00445874","article-title":"Gene amplification in yeast: CUP1 copy number regulates copper resistance","volume":"7","author":"Fogel","year":"1983","journal-title":"Curr. Genet."},{"key":"2026050612440116100_R21","doi-asserted-by":"crossref","first-page":"5342","DOI":"10.1073\/pnas.79.17.5342","article-title":"Tandem gene amplification mediates copper resistance in yeast","volume":"79","author":"Fogel","year":"1982","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026050612440116100_R22","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1534\/genetics.114.171124","article-title":"Too much of a good thing: the unique and repeated paths toward copper adaptation","volume":"199","author":"Gerstein","year":"2015","journal-title":"Genetics"},{"key":"2026050612440116100_R23","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1099\/mic.0.058024-0","article-title":"Amplification of the CUP1 gene is associated with evolution of copper tolerance in Saccharomyces cerevisiae","volume":"158","author":"Adamo","year":"2012","journal-title":"Microbiology"},{"key":"2026050612440116100_R24","doi-asserted-by":"crossref","first-page":"E5046","DOI":"10.1073\/pnas.1801040115","article-title":"The genome-wide rate and spectrum of spontaneous mutations differ between haploid and diploid yeast","volume":"115","author":"Sharp","year":"2018","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026050612440116100_R25","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2026050612440116100_R26","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1101\/gr.129684.111","article-title":"VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing","volume":"22","author":"Koboldt","year":"2012","journal-title":"Genome Res."},{"key":"2026050612440116100_R27","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"2026050612440116100_R28","unstructured":"R Core Team\n          . 2021R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing. Seehttps:\/\/www.R-project.org\/."},{"key":"2026050612440116100_R29","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v067.i01","article-title":"Fitting linear mixed-effects models using lme4","volume":"67","author":"Bates","year":"2015","journal-title":"J. Stat. Softw"},{"key":"2026050612440116100_R30","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.1016\/j.csda.2007.10.022","article-title":"Size and power of tests for a zero random effect variance or polynomial regression in additive and linear mixed models","volume":"52","author":"Scheipl","year":"2008","journal-title":"Comput. Stat. Data Anal."},{"key":"2026050612440116100_R31","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pbio.2001333","article-title":"Environmental change drives accelerated adaptation through stimulated copy number variation","volume":"15","author":"Hull","year":"2017","journal-title":"PLoS Biol."},{"key":"2026050612440116100_R32","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1126\/science.1116102","article-title":"Recombination regulation by transcription-induced cohesin dissociation in rDNA repeats","volume":"309","author":"Kobayashi","year":"2005","journal-title":"Science"},{"key":"2026050612440116100_R33","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1128\/MCB.18.5.2514","article-title":"Dynamic regulation of copper uptake and detoxification genes in Saccharomyces cerevisiae","volume":"18","author":"Pen\u0303a","year":"1998","journal-title":"Mol. Cell. Biol."},{"key":"2026050612440116100_R34","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1074\/jbc.M609535200","article-title":"A cadmium-transporting P1B-type ATPase in yeast Saccharomyces cerevisiae","volume":"282","author":"Adle","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2026050612440116100_R35","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1039\/c0mt00035c","article-title":"High density array screening to identify the genetic requirements for transition metal tolerance in Saccharomyces cerevisiae","volume":"3","author":"Bleackley","year":"2011","journal-title":"Metallomics"},{"key":"2026050612440116100_R36","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1534\/genetics.113.159202","article-title":"The sister chromatid cohesion pathway suppresses multiple chromosome gain and chromosome amplification","volume":"196","author":"Covo","year":"2014","journal-title":"Genetics"},{"key":"2026050612440116100_R37","first-page":"4091","article-title":"The CUP2 gene product, regulator of yeast metallothionein expression, is a copper-activated DNA-binding protein","volume":"9","author":"Buchman","year":"1989","journal-title":"Mol. Cell. Biol."},{"key":"2026050612440116100_R38","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2505337122","article-title":"Evolution of cross-tolerance to metals in yeast","volume":"122","author":"Bazzicalupo","year":"2025","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026050612440116100_R39","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1534\/genetics.117.201285","article-title":"Properties of mitotic and meiotic recombination in the tandemly-repeated CUP1 gene cluster in the yeast Saccharomyces cerevisiae","volume":"206","author":"Zhao","year":"2017","journal-title":"Genetics"},{"key":"2026050612440116100_R40","doi-asserted-by":"crossref","first-page":"9272","DOI":"10.1073\/pnas.0803466105","article-title":"A genome-wide view of the spectrum of spontaneous mutations in yeast","volume":"105","author":"Lynch","year":"2008","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026050612440116100_R41","doi-asserted-by":"crossref","first-page":"2210","DOI":"10.1073\/pnas.1406847111","article-title":"Genome-wide high-resolution mapping of chromosome fragile sites in  Saccharomyces cerevisiae","volume":"111","author":"Song","year":"2014","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2026050612440116100_R42","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1093\/genetics\/147.4.1533","article-title":"RDH54, a RAD54 homologue in Saccharomyces cerevisiae, is required for mitotic diploid-specific recombination and repair and for meiosis","volume":"147","author":"Klein","year":"1997","journal-title":"Genetics"},{"key":"2026050612440116100_R43","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1023\/A:1017034925212","article-title":"How should we explain variation in the genetic variance of traits?","volume":"102\u2013103","author":"Houle","year":"1998","journal-title":"Genetica"},{"key":"2026050612440116100_R44","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1146\/annurev-micro-030117-020444","article-title":"Copper acquisition and utilization in fungi","volume":"71","author":"Smith","year":"2017","journal-title":"Annu. Rev. Microbiol."},{"key":"2026050612440116100_R45","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.01581","article-title":"Endogenous RNA interference is driven by copy number","volume":"3","author":"Cruz","year":"2014","journal-title":"eLife"},{"key":"2026050612440116100_R46","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/s41586-018-0030-5","article-title":"Genome evolution across 1,011 Saccharomyces cerevisiae isolates","volume":"556","author":"Peter","year":"2018","journal-title":"Nature"},{"key":"2026050612440116100_R47","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pgen.1010692","article-title":"SO2 and copper tolerance exhibit an evolutionary trade-off in Saccharomyces cerevisiae","volume":"19","author":"Onetto","year":"2023","journal-title":"PLoS Genet."},{"key":"2026050612440116100_R48","article-title":"Data from: the effect of spontaneous mutations on CUP1 copy number and copper tolerance in Saccharomyces cerevisiae. Figshare.","author":"Sohoni","year":"2026"},{"key":"2026050612440116100_R49","article-title":"Supplementary material from: The effect of spontaneous mutations on CUP1 copy number and copper tolerance in Saccharomyces cerevisiae. FigShare.","author":"Sohoni","year":"2026"}],"container-title":["Biology Letters"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/royalsocietypublishing.org\/rsbl\/article-pdf\/doi\/10.1098\/rsbl.2026.0090\/6136064\/rsbl.2026.0090.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/royalsocietypublishing.org\/rsbl\/article-pdf\/doi\/10.1098\/rsbl.2026.0090\/6136064\/rsbl.2026.0090.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T16:44:15Z","timestamp":1778085855000},"score":1,"resource":{"primary":{"URL":"https:\/\/royalsocietypublishing.org\/rsbl\/article\/22\/5\/20260090\/481583\/The-effect-of-spontaneous-mutations-on-CUP1-copy"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,6]]},"references-count":49,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,5,6]]}},"URL":"https:\/\/doi.org\/10.1098\/rsbl.2026.0090","relation":{},"ISSN":["1744-957X"],"issn-type":[{"value":"1744-957X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,6]]},"article-number":"20260090"}}