{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/246693"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/246693","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Understanding the epigenome using system genetics","abstract":"Genetics has been successful in associating DNA sequence variants to both dichotomous and continuous traits in a variety of organisms, from plant and farm animal studies to human disease. With the advent of high-throughput genotyping, there has been an almost routine gen- eration of genome-wide association studies (GWAS) between human disease traits and genomic regions. Despite this success, a particular frustration is that the majority of associated loci are in non-coding regions of the genome and thus interpretation is hard. To improve characterisation of non-coding regions, molecular as- says can be used as a phenotype, and subsequently be used to explain how genetics alter molecular mechanisms. In this thesis, the inter- play of three molecular assays that are involved in regulating gene expression is studied. On 60 individuals, several assays are performed: FAIRE-chip, CTCF- seq, RNA-seq and DNA-seq. In the first part, the discovery and characteristics of FAIRE-QTLs is presented. The identified FAIRE-QTLs show strong overlap with other molecular QTLs, histone modifications, and transcription factors. The second part consists of the integration of genome-wide molecu- lar assays in a human population to reconstruct the human epigenome. Each of the molecular assays is associated with each of the other assays to discover phenotype-to-phenotype correlations. Furthermore, QTL data are used to dissect the causality for these phenotype-to-phenotype correlations in a system genetic manner. The third part presents a comprehensive view of CTCF binding on the X chromosome, and its implications for X-chromosome inactivation. A novel X chromosome-wide CTCF effect is observed. Using the gender of each of the cell lines, observations are made about which CTCF sites are dosage-compensated, active on both chromosomes, or are only bound in females.","abstract_html":"Genetics has been successful in associating DNA sequence variants to both dichotomous and continuous traits in a variety of organisms, from plant and farm animal studies to human disease. With the advent of high-throughput genotyping, there has been an almost routine gen- eration of genome-wide association studies (GWAS) between human disease traits and genomic regions. Despite this success, a particular frustration is that the majority of associated loci are in non-coding regions of the genome and thus interpretation is hard. To improve characterisation of non-coding regions, molecular as- says can be used as a phenotype, and subsequently be used to explain how genetics alter molecular mechanisms. In this thesis, the inter- play of three molecular assays that are involved in regulating gene expression is studied. On 60 individuals, several assays are performed: FAIRE-chip, CTCF- seq, RNA-seq and DNA-seq. In the first part, the discovery and characteristics of FAIRE-QTLs is presented. The identified FAIRE-QTLs show strong overlap with other molecular QTLs, histone modifications, and transcription factors. The second part consists of the integration of genome-wide molecu- lar assays in a human population to reconstruct the human epigenome. Each of the molecular assays is associated with each of the other assays to discover phenotype-to-phenotype correlations. Furthermore, QTL data are used to dissect the causality for these phenotype-to-phenotype correlations in a system genetic manner. The third part presents a comprehensive view of CTCF binding on the X chromosome, and its implications for X-chromosome inactivation. A novel X chromosome-wide CTCF effect is observed. Using the gender of each of the cell lines, observations are made about which CTCF sites are dosage-compensated, active on both chromosomes, or are only bound in females.","abstract_has_math":false,"creators":["Timmer, Sander Willem"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-01-06","date_published":"2015-01-06","updated_at":"2026-07-22T22:24:16Z","subjects":["genetics","epigenetics","gwas","dna","gene regulation"],"languages":["en"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ca782970-145f-4d0b-894e-38d1c0de09ae/download"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.15988","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Timmer, Sander Willem"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2015-01-06"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/246693"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["genetics","epigenetics","gwas","dna","gene regulation"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/ca782970-145f-4d0b-894e-38d1c0de09ae/download"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.15988"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c6b0ab5e-c9cd-499f-8ff6-cb6194581f33/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Genetics has been successful in associating DNA sequence variants to both dichotomous and continuous traits in a variety of organisms, from plant and farm animal studies to human disease. 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