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Accelerated Adaptation through Stimulated Copy Number Variation in Saccharomyces cerevisiae

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cam.restrictionthesis_access_open
cam.supervisorHouseley, Jonathan
cam.supervisor.orcidHouseley, Jonathan [0000-0001-8509-1500]
cam.thesis.fundingtrue
dc.contributor.authorHull, Ryan
dc.contributor.orcidHull, Ryan [0000-0001-7153-4198]
dc.date.accessioned2018-10-25T08:51:41Z
dc.date.available2018-10-25T08:51:41Z
dc.date.issued2018-11-24
dc.date.submitted2018-04-19
dc.date.updated2018-10-24T12:41:15Z
dc.description.abstractAccelerated Adaptation through Stimulated Copy Number Variation in Saccharomyces cerevisiae Ryan Matthew Hull Repetitive regions of the genome, such as the centromeres, telomeres and ribosomal DNA account for a large proportion of the genetic variation between individuals. Differences in the number of repeat sequences between individuals is termed copy number variation (CNV) and is rife across eukaryotic genomes. CNV is of clinical importance as it has been implicated in many human disorders, in particularly cancers where is has been associated with tumour growth and drug resistance. The copper-resistance gene CUP1 in Saccharomyces cerevisiae is one such CNV gene. CUP1 is transcribed from a copper inducible promoter and encodes a protein involved in copper detoxification. In this work I show that yeast can regulate their repeat levels of the CUP1 gene through a transcriptionally stimulated CNV mechanism, as a direct adaptation response to a hostile environment. I characterise the requirement of the epigenetic mark Histone H3 Lysine 56 acetylation (H3K56ac) for stimulated CNV and its limitation of only working at actively transcribed genes. Based upon my findings, I propose a model for how stimulated CNV is regulated in yeast and show how we can pharmacologically manipulate this mechanism using drugs, like nicotinamide and rapamycin, to stimulate and repress a cell’s ability to adapt to its environment. I further show that the model is not limited to high-copy CUP1 repeat arrays, but is also applicable to low-copy systems. Finally, I show that the model extends to other genetic loci in response to different challenging environments, such as formaldehyde stimulation of the formaldehyde-resistance gene SFA1. To the best of our knowledge, this is the first example of any eukaryotic cell undergoing genome optimisation as a novel means to accelerate its adaptation in direct response to its environment. If conserved in higher eukaryotes, such a mechanism could have major implications in how we consider and treat disorders associated with changes in CNV.
dc.identifier.doi10.17863/CAM.31757
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/284381
dc.language.isoen
dc.publisher.collegeHomerton College
dc.publisher.departmentBabraham Institute
dc.publisher.institutionUniversity of Cambridge
dc.rightsAll rights reserved
dc.rightsAll Rights Reserveden
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved/en
dc.subjectCopy Number Variation
dc.subjectAdaptation
dc.subjectCUP1
dc.subjectSFA1
dc.subjectHistone H3 Lysine 56
dc.subjectSaccharomyces cerevisiae
dc.subjectCopper
dc.subjectFormaldehyde
dc.subjectNicotinamide
dc.subjectRtt109
dc.subjectRapamycin
dc.subjectMutation
dc.subjecteccDNA
dc.subjectDNA Damage
dc.subjectReplisome
dc.subjectBreak-induced replication
dc.titleAccelerated Adaptation through Stimulated Copy Number Variation in Saccharomyces cerevisiae
dc.typeThesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnameDoctor of Philosophy (PhD)
dc.type.qualificationtitlePhD in Biological Science at Babraham Institute

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