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Title: Evolution and gene regulation of the genomic imprinting mechanism
Author: Mungall, Andrew James
ISNI:       0000 0001 3431 468X
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2007
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Genomic imprinting describes an epigenetic mechanism by which genes are active or silent depending on their parental origin. Imprinting exists in plants and mammals, but how this monoallelic expression mechanism has evolved is not understood at the molecular leveL Here I describe the mapping, sequencing and analysis of vertebrate orthologous imprinted regions spanning 11.5 Mb of genomic sequence from species with and without genomic imprinting. In eutherian (placental) mammals, imprinting can be regulated by differential DNA methylation, non-coding RNAs, enhancers and insulator elements. The systematic sequence comparison of the IGF2-HI9 imprinting cluster, in eutherians and marsupials (tammar wallaby and opossum), has revealed the presence of the enigmatic noncoding Ri'JA H19 in marsupials. Furthermore, we have characterised the marsupial / H19 expression status and identified key regulatory elements required for the germline imprinting of the neighbouring IGF2 gene. All the major hallmarks of the imprinting mechanism of the IGF2-HI9 locus were found to be conserved in therian mammals. In mammals, this imprinting system is therefore the most conserved germline derived epigenetic mechanism discovered so far. The high-quality genomic sequences have provided early glimpses of the genomic landscapes for species such as the monotreme platypus and marsupial tammar wallaby for which little was previously known. Comparative sequence analysis was used to identify candidate regulatory elements in the neighbouring imprinting centre 1 and 2 regions of human chromosome llp1S.5. Nine novel enhancer elements were identified following in zitro gene-reporter assays and correlation of conserved sequences with recent ENCODE data revealed probable functions for a further 24 elements.
Supervisor: Not available Sponsor: Not available
Qualification Name: Open University, 2007 Qualification Level: Doctoral
EThOS ID:  DOI: Not available