{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/312443"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/312443","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"The evolutionary genomics of CTCF binding and functional signatures in mouse.","abstract":"Genetic differences within and between species predominantly lie in the noncoding sequence of the regulatory regions of the genome whose function and significance largely remain poorly understood. Despite significant progress in the field of genomics and the rapid progress in sequencing methods and the subsequent explosion of genomic data, our understanding of the role of the non- coding genetic sequence in the regulation of tissue- and species-specific gene expression is still lagging behind, limiting our comprehension of the evolutionary mechanisms and pressures that shape those expression profiles, and their involvement in the health and disease. The CTCF protein demarcates mammalian genomes into discrete transcriptionally active domains, providing the platform for complex spatial and temporal regulatory processing of genetic information that govern biological processes. In this thesis, I investigate the dynamics and functional implications of evolutionarily novel CTCF binding sites in two Mus genus mouse subspecies, Mus musculus domesticus and Mus musculus castaneus, separated by a short evolutionary time of only one million years. The project investigated the subspecies-specific binding of CTCF in terms of the repeat content, evolution, functional impact and involvement in chromatin conformation. The key findings of this investigation are: (1) the incorporation of young CTCF sites into the non-coding genome via action of transposable elements is followed rapidly with the exhibition of various characteristics of biological function; (2) Unlike other tissue-specific transcription factors, allele- specific CTCF occupancy is affected by cis- and trans-acting regulatory mechanisms that exhibit similar functional characteristics; (3) CTCF evolutionary dynamics support both maintenance of pre-existing structures and functions and provide template for novel ones. In summary, this thesis discusses the evolutionary dynamics of CTCF genomic occupancy and functional signatures in short evolutionary time, and illustrates how either novel species-specific CTCF sites, or common sites with newly-acquired genotypic variants integrate into existing genomic architecture and begin to exert their effects.","abstract_html":"Genetic differences within and between species predominantly lie in the noncoding sequence of the regulatory regions of the genome whose function and significance largely remain poorly understood. Despite significant progress in the field of genomics and the rapid progress in sequencing methods and the subsequent explosion of genomic data, our understanding of the role of the non- coding genetic sequence in the regulation of tissue- and species-specific gene expression is still lagging behind, limiting our comprehension of the evolutionary mechanisms and pressures that shape those expression profiles, and their involvement in the health and disease. The CTCF protein demarcates mammalian genomes into discrete transcriptionally active domains, providing the platform for complex spatial and temporal regulatory processing of genetic information that govern biological processes. In this thesis, I investigate the dynamics and functional implications of evolutionarily novel CTCF binding sites in two Mus genus mouse subspecies, Mus musculus domesticus and Mus musculus castaneus, separated by a short evolutionary time of only one million years. The project investigated the subspecies-specific binding of CTCF in terms of the repeat content, evolution, functional impact and involvement in chromatin conformation. The key findings of this investigation are: (1) the incorporation of young CTCF sites into the non-coding genome via action of transposable elements is followed rapidly with the exhibition of various characteristics of biological function; (2) Unlike other tissue-specific transcription factors, allele- specific CTCF occupancy is affected by cis- and trans-acting regulatory mechanisms that exhibit similar functional characteristics; (3) CTCF evolutionary dynamics support both maintenance of pre-existing structures and functions and provide template for novel ones. In summary, this thesis discusses the evolutionary dynamics of CTCF genomic occupancy and functional signatures in short evolutionary time, and illustrates how either novel species-specific CTCF sites, or common sites with newly-acquired genotypic variants integrate into existing genomic architecture and begin to exert their effects.","abstract_has_math":false,"creators":["Azazi, Dhoyazan Mohammed Ali"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Flicek, Paul"],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-02-24","date_published":"2020-02-24","updated_at":"2026-07-22T22:24:32Z","subjects":["Comparative Genomics","Evolutionary Genomics","Regulation of Gene Expression","CTCF","Computational Biology"],"languages":["eng"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/0342cfce-8443-4019-bd19-4fee80bd55ae/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.59535","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Flicek, Paul"]},{"key":"dc:creator","label":"Author","values":["Azazi, Dhoyazan Mohammed Ali"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2020-02-24"]},{"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/1810/312443"]},{"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":["Comparative Genomics","Evolutionary Genomics","Regulation of Gene Expression","CTCF","Computational Biology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/0342cfce-8443-4019-bd19-4fee80bd55ae/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.59535"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a50c4343-6c03-4d8b-b435-7baf0a37ec58/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Genetic differences within and between species predominantly lie in the noncoding sequence of the regulatory regions of the genome whose function and significance largely remain poorly understood. 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The project investigated the subspecies-specific binding of CTCF in terms of the repeat content, evolution, functional impact and involvement in chromatin conformation. The key findings of this investigation are: (1) the incorporation of young CTCF sites into the non-coding genome via action of transposable elements is followed rapidly with the exhibition of various characteristics of biological function; (2) Unlike other tissue-specific transcription factors, allele- specific CTCF occupancy is affected by cis- and trans-acting regulatory mechanisms that exhibit similar functional characteristics; (3) CTCF evolutionary dynamics support both maintenance of pre-existing structures and functions and provide template for novel ones. 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