Year: 2013
Type: dissertation
Study design: Observational Study
Abstract: The field of human epigenetics has become widely accepted, yet many basic principles remain unclear. It is important to determine the extent to which DNA methylation profiles are influenced by DNA sequence; we addressed this question using tissues from human monozygotic (MZ) and dizygotic (DZ) twins, post-mortem brain and germline samples. First, we analyzed white blood cells (WBC), buccal epithelium, and rectal biopsies from MZ twins, and annotated the epigenetic metastability of ~6,000 unique genomic regions. Our study was the first to utilize epigenome-wide profiling to document DNA methylation differences in MZ twins. We also found that DZ twins exhibited more epigenetic differences compared to MZ twins. Two competing hypotheses were tested: 1) DNA sequence differences caused the additional DZ epigenetic variation, or 2) additional epigenetic differences are present in the zygotes of DZ co-twins. Our animal and in silico studies supported hypothesis 2, providing the first evidence for twin-based epigenetic heritability. Still, genetic impact on epigenetic variation cannot be excluded. To explore DNA–epigenetic interactions and their role in disease, we mapped allele-specific methylation (ASM) in brain and sperm DNA from individuals affected with major psychosis and controls. We found that ~2.5% of brain SNPs show ASM, although genomic distribution of these “epiSNPs” varies between cohorts. EpiSNPs were generally enriched in untranslated regions (UTRs) and regions surrounding genes, and depleted in exons. The schizophrenia cohort contained twice as many epiSNPs as controls and bipolar disorder, although they largely overlapped. Most epiSNP Gene Ontology categories were related to brain development and function; differences between cohorts were observed in glutamate and insulin pathways. Tissue-specific epiSNPs were also detected in sperm DNA. Deep sequencing analysis revealed that any SNP could potentially demonstrate low-level ASM. This work describes various aspects of genetic–epigenetic interactions, while supporting epigenetic heritability and the role of genetic-epigenetic interactions in major psychiatric disease.
Source: TSpace (University of Toronto)
Author: Ptak, Carolyn
Institution: University of Toronto
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2331308536