Genes are typically expressed in equal amounts from both parentally inherited
chromosomes. However, recent studies have demonstrated that genes can be preferentially
transcribed from a locus. Non-random preferential expression of alleles can occur in a parent-of-origin pattern, known as imprinting, where epigenetic factors regulate their transcription. Alternatively, it can occur in a haplotype-specific pattern, where cis-acting
polymorphisms in regulatory regions are thought to underlie the phenomenon. Both forms of unequal allelic expression have been associated with human disease. Consequently, it is important to identify genes subject to unequal allelic expression and characterize mechanisms that regulate differential transcription.
This thesis presents the results of a screen for unequal allelic expression where
approximately 50 murine transcripts homologous to genes on human chromosome 7 were analyzed. Human chromosome 7 was selected due to its association with several human disorders that show parent-of-origin effects. The screen identified non-imprinted
preferential allelic expression in numerous transcripts and demonstrated that such patterns can occur in tissue specific patterns.
Paraoxonase-1 (Pon1), a gene implicated in arthrosclerosis, was identified as having
a dynamic pattern of allelic expression which varies throughout embryonic development. This finding represents the first report of a developmentally regulated pattern of allelic variance. Carboxypeptidase-A4 (Cpa4) was identified as having a tissue-specific imprinted
pattern of expression, where the maternal allele was preferentially expressed in all
embryonic tissues, with the exception of the brain. The Krüppel-like factor 14 gene (Klf14), a novel imprinted transcript, was found to have ubiquitous maternal expression in all human and murine tissues analyzed. A differentially methylated region, generally
associated with imprinted transcripts, was not found in the gene’s CpG island, nor was a
differential pattern of histone modifications identified. However, it was determined that maternal methylation regulates the transcript.
The data in this thesis contribute to our understanding of the numerous patterns of
allelic expression that exist in nature and the diverse mechanisms that regulate them.
Ultimately, quantitative analyses of allelic expression patterns and the identification of their underlying genomic DNA sequences will become standard protocol in all biomedical studies.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/11216 |
| Date | 31 July 2008 |
| Creators | Katiraee, Layla |
| Contributors | Scherer, Stephen W. |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
| Format | 2144586 bytes, application/pdf |
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