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Predictive models of enhancer-gene regulation
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Nasser, Joseph (2021) Predictive models of enhancer-gene regulation. PhD thesis, University of Warwick.
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Official URL: http://webcat.warwick.ac.uk/record=b3816010
Abstract
Enhancers are DNA elements which play crucial roles in the spatio-temporal regulation of gene expression. An open question in enhancer biology is to identify which enhancers regulate which genes in which cell types. Recent experimental advances have enabled the design of high throughput screens to functionally interrogate putative enhancer-gene connections. These datasets have facilitated the development of predictive models of enhancer-gene regulation.
The main contribution of this thesis is an in depth analysis of the predictive ability of a specific enhancer-gene prediction method known as the Activity-by- Contact (ABC) model. We show that ABC is an effective predictor and outperforms other previously published prediction methods. We consider variations of the score which help to illustrate why the model performs so well. We consider the implications of success of the model on the role of genome architecture in gene regulation.
The ABC model is practically implementable and we describe how it was used to generate a database of enhancer-gene predictions across 131 cell types. We illustrate case studies which describe how this database can be used to interpret non-coding human genetic variation.
We discuss recent advances in single-cell sequencing which may form the basis for future larger-scale enhancer screens. We highlight a power-calculation that must be conducted to design such an experiment.
We also consider a formal mathematical representation of the ABC model. We show that the mathematical model is tractable and compute the mean of the mRNA distribution under this model. We show how the ABC Score formula can be derived from the mathematical model and generally describe the relationship between conceptual modeling and formal modeling.
We conclude by discussing the importance of these results within the _eld of gene regulation as a whole.
Item Type: | Thesis (PhD) | ||||
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Subjects: | Q Science > QH Natural history > QH426 Genetics | ||||
Library of Congress Subject Headings (LCSH): | Gene expression, Genetic regulation, Promoters (Genetics), Genomes, Nucleotide sequence, Sequence alignment (Bioinformatics) | ||||
Official Date: | December 2021 | ||||
Dates: |
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Institution: | University of Warwick | ||||
Theses Department: | Warwick Medical School | ||||
Thesis Type: | PhD | ||||
Publication Status: | Unpublished | ||||
Supervisor(s)/Advisor: | Ott, Sascha | ||||
Format of File: | |||||
Extent: | vi, 58 leaves : colour illustrations, charts | ||||
Language: | eng |
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