Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581372
Title: Genome-wide DNaseI hypersensitive sites profiles in laboratory mouse strains by DNase-seq
Author: Hosseini, Mona
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2013
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Abstract:
Variation at regulatory elements, identified through hypersensitivity to digestion by Deoxyribonuclease I (DNase I), is believed to contribute to variation in complex traits, but the extent and consequences of this variation are poorly characterized. To investigate the relationship between sequence variation, and the functional consequences of variation in chromatin accessibility, genome-wide DNase I hypersensitive sites (DHS) of terminally differentiated erythroblasts were studied in eight inbred strains of mice studied (A/J, AKR/J, BALBc/J, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, and LP/J). These strains were selected because of the availability of their genome sequence and quantitative trait loci (QTL) data. After confirming that next generation sequencing could identify DNase I hypersensitive sites with high sensitivity and specificity, and that differential peaks could be found, an automated peak calling pipeline was developed and optimized. 36,693 DHS peaks were identified covering 9.1 Mb (0.29%) of mouse genome. There was no indication of within strain variation. Between strains reproducible variation was observed at approximately 5% of DNase hypersensitive sites (1,397 DHSs). Variable DHSs were more likely to be enhancers than promoters and less likely to occur at conserved regions of the genome. Only 36% of such variable DHSs contain a sequence variant predictive of site variation and 12% contain at least one variant that disrupts transcription factor binding sites. The majority (86%) of variable DHSs differ in size/shape and the remaining 14% demonstrate discrete variation in single peak or cluster of peaks. Sequence variants within variable DHS are more likely to be associated with complex traits than those in non-variant DHS, and variants associated with complex traits preferentially occur in enhancer-like elements. Changes at a small proportion (7%) of discretely variable DHS are associated with changes in nearby transcriptional activity. Our results show that whilst DNA sequence variation is not the major determinant of variation in open chromatin, where such variants exist they are likely to be causal for complex traits.
Supervisor: Flint, Jonathan Sponsor: Wellcome Trust ; Clarendon Fund
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.581372  DOI: Not available
Keywords: Medical Sciences ; Genetics (medical sciences) ; Mathematical genetics and bioinformatics (statistics) ; DNaseI hypersensitive sites ; DNase-seq ; inbred mice ; chromatin variation
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