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IDENTIFYING ALLELE-SPECIFIC DNA METHYLATION IN MAMMALIAN GENOMES
by
Fang Fang
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(COMPUTATIONAL BIOLOGY AND BIOINFORMATICS)
December 2012
Copyright 2012 Fang Fang
Object Description
| Title | Identifying allele-specific DNA methylation in mammalian genomes |
| Author | Fang, Fang |
| Author email | ffang@usc.edu;fang.flora@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Computational Biology and Bioinformatics |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2012-08-13 |
| Date submitted | 2012-09-13 |
| Date approved | 2012-09-13 |
| Restricted until | 2012-09-13 |
| Date published | 2012-09-13 |
| Advisor (committee chair) | Smith, Andrew D. |
| Advisor (committee member) |
Tavaré, Simon Tavare, Simon Pellegrini, Matteo Hacia, Joseph G. |
| Abstract | Among the most well-known functions of DNA methylation is in mediating imprinted gene expression by differentially marking specific regulatory regions on maternal and paternal alleles. Imprinted genes are expressed from one of the two parental alleles in mammals, thereby rendering the organism functionally haploid. Imprinting has been tied to the evolution of placental mammals and defects in imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remains largely untapped in the study of imprinting. We present a novel statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for full-genome ASM profiling based on our model. Because our method is independent of genotype, it is applicable to identify ASM in the context of genomic imprinting. ❧ We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Novel predicted regions of ASM common to multiple cell types frequently mark ncRNA promoters and represent promising starting points for targeted validation. ❧ We also compared regions of ASM between uncultured mouse and human cells. Regions with both conserved sequence and ASM status between species show high concordance of known imprinted genes, adding more evidence for novel prediction of imprinted genes. The skewing of ASM associated imprinted genes in mouse agrees with the parental conflict theory, which hypothesizes that the evolution of genomic imprinting is inspired by the different interests of parental genes on the offspring growth. Furthermore, the variation of ASM between species shows that ASM set in parental germlines play more critical roles in regulating imprinting than those set in somatic cells. ❧ More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species. |
| Keyword | allele-specific methylation; bisulfite sequencing; epigenetics; genomic imprinting; imprinting control regions |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Fang, Fang |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@dots.usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-FangFang-1196.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | IDENTIFYING ALLELE-SPECIFIC DNA METHYLATION IN MAMMALIAN GENOMES by Fang Fang A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (COMPUTATIONAL BIOLOGY AND BIOINFORMATICS) December 2012 Copyright 2012 Fang Fang |
