Identification of New Human Imprinted Genes: A Novel Approach

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"Imprinted" genes are critical for normal human growth and development. Almost all of our genes occur in pairs, with one copy of each gene pair inherited from our mother (maternal) and the other from our father (paternal). For the vast majority of our gene pairs, the copy inherited from each parent is expressed equally. However, imprinted genes are expressed in a parent of origin-specific manner. That is, the genes are transcribed (read) from either the maternal or paternal copy, not both, and the expression of these genes may differ in specific tissues. The mechanism by which this special type of transcription is achieved is termed epigenetic. Epigenetic marks, such as DNA methylation, essentially silence the gene by making it inaccessible to the transcription machinery in the cell. Imprinted genes typically have opposite epigenetic marks on the two parental genes in the pair, one methylated (silenced) and the other not methylated (transcribed). This is called differential DNA methylation. Of the approximately 25,000 genes in every human cell, there are only 62 imprinted genes identified to date. Our hypothesis is that there are more human imprinted genes than the 62 that have already been identified. We have developed a novel approach to directly identify new imprinted genes in humans. This approach utilizes rare human tissues that carry some or all of their genes from only one parent, either mother or father; this is termed uniparental (one parent) disomy (two copies). We have demonstrated that comparing DNA methylation in these uniparental tissues to normal biparental tissues allows us to identify differential DNA methylation marks that are characteristic of imprinted genes. Using this approach and new state-of-the-art technology, we will capture new candidate imprinted genes. We expect that these experiments will increase the number of identified human imprinted genes and will ultimately enhance our understanding of how their regulation functions to guide normal human development.