A Whole-Genome Screen for Novel Imprinted Loci (WGimprint)
A Whole-Genome Screen for Novel Imprinted Loci
Start date: Apr 1, 2008,
End date: Mar 31, 2010
First, I propose to identify all imprinted loci in humans. I will perform a whole-genome screen using high-density oligonucleotide microarrays coupled with immunoprecipitation of methylated DNA to compare the methylation patterns in rare uniparental tissues. I have obtained samples from complete hydatidiform moles, which have an exclusively paternal genetic contribution, and ovarian teratomas, which have an exclusively maternal genetic contribution. I demonstrate that the study of genomic methylation in these two tissues enables the direct comparison of a maternally methylated genome versus a paternally methylated genome, representing an optimized system for the detection of novel imprinted loci. Second, I will use this imprinting map to perform a preliminary investigation of the role of epigenetic defects in disorders of human development. I hypothesise that the study of genomic methylation patterns in connection with human disease represents a rich and largely untapped area of genetic research. I will investigate methylation patterns in a cohort of monozygotic twins who show discordant developmental phenotypes. As monozygotic twins are genetically identical, the study of twin pairs who present with phenotypic differences represents a highly sensitized population for the identification of epigenetic errors associated with human disease. This proposal harnesses a new generation of high-density oligonucleotide arrays which allow for the first time the entire human genome to be investigated at the necessary resolution to systematically uncover novel imprinted genes. The proposal will give ample opportunity to acquire new experimental, theoretical and computational knowledge, and also to develop the novel research area of ‘Methylomics’ in human genetics.
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