Sequencing the complex and the regulatory regions of the human genome
Abstract/Contents
- Abstract
- While huge technological and scientific advances in human genomics have been made in the recent decade, critical questions still remain. In this dissertation, we focus on two problems: Determining variants within highly homologous regions of the human genome; Sequencing and quantification of differences in human regulatory regions. Core to the first problem is the lack of a scalable sequencing technology with sufficiently long read length and accuracy to enable truly unique mapping. Here we present our novel method, RFA, to confidently align short reads in highly homologous regions and enable accurate variant discovery in a cost-effective fashion by exploiting, via a Markov Random Field, the dependency among the short reads generated by a long read in read cloud technology. We test our method through both extensive simulations and experimental validation. We demonstrate that our method accurately recovers variation in 155Mbp of the human genome, including 94% of 67Mbp of segmental duplication sequence and 96% of 11Mbp of transcribed sequence that are currently hidden from short read technologies. To shed light on the second question, we study differences in chromatin state across 19 diverse individuals using six histone modifications, cohesin, Pol2 and CTCF in lymphoblastoid lines. We find extensive regulatory region differences in both activity (strong vs. weak vs. poised) and identity (enhancers vs. promoters vs. repressed regions). Enhancer activity is particularly diverse among individuals, and is divergent across populations in regions associated with signals of positive selection. Differences in modifications are inherited in trios and correlate with gene expression differences, indicating that they have functional consequences. Finally, differences in regulatory elements often reside in the same large chromosomal topological domains. Overall, our results provide fundamental insights into genetic and epigenetic differences of humans and how regulatory elements might evolve within a species.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2018; ©2018 |
| Publication date | 2018; 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Liu, Yuling |
|---|---|
| Degree supervisor | Batzoglou, Serafim |
| Degree supervisor | Markland, Thomas E |
| Thesis advisor | Batzoglou, Serafim |
| Thesis advisor | Markland, Thomas E |
| Thesis advisor | Sherlock, Gavin |
| Degree committee member | Sherlock, Gavin |
| Associated with | Stanford University, Department of Chemistry. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Yuling Liu. |
|---|---|
| Note | Submitted to the Department of Chemistry. |
| Thesis | Thesis Ph.D. Stanford University 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Yuling Liu
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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