Genomic or parental imprinting is defined as the parent-of-origin monoallelic gene expression as a result of epigenetic modification. Several human diseases and syndromes are caused by the inappropriate disruption of genomic imprinting. To elucidate the origins of genomic imprinting and further our understanding of the regulation of parental specific gene expression we are undertaking comparative mapping and sequencing in chicken, platypus and wallaby in orthologous regions of well defined imprinting cluster regions of mouse and human. Comparative sequence analysis of vertebrates with imprinting (human, mouse and the marsupial Tammar wallaby) and those apparently lacking imprinting (chicken and the monotreme platypus) is expected to reveal conserved sequences, including functional elements involved in the imprinting mechanism.

Phylogeny of vertebrate species. Mammals are divided into three groups; Monotremes, Marsupials and Eutherians. Eutherian mammals diverged approximately 148 million years (Myr) ago from the marsupial mammals, which in turn diverged from the egg-laying monotremes approximately 166 Myr ago. The apparent absence of genomic imprinting in monotremes and presence in marsupials suggests that the function and mechanism of imprinting evolved between 148 and 166 Myr ago and may have co-evolved with placentation. Divergence times taken from Bininda-Emonds et al. 2007 and Kumar and Hedges 1998.

Although BAC libraries are becoming available for a growing number of species, few of these genomes have adequate marker coverage required for the development of sequence-ready maps. Highly conserved sequences between distantly related species have therefore been used to design hybridisation probes for library screening. Identified BACs have been assembled into contigs by restriction enzyme fingerprinting and landmark content analysis and minimal tiling paths selected for sequencing. Multi-species comparative sequence analysis in the regions of conserved synteny to human 11p15.5 has revealed highly conserved sequences lying outside annotated coding regions. These candidate functional elements will be tested for promoter, enhancer, silencer and insulator activities in reporter assays and selected elements will be studied in knockout mice and subjected to genetic and epigenetic analysis in imprinting diseases.

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