DESCRIPTION (provided by applicant): In diploid eukaryotic organisms it is generally assumed that the maternally and paternally derived copies of each gene are simultaneously expressed at comparable levels and are replicated during the same portion of S phase. However there are exceptions where one of the two copies is not expressed and the two copies are asynchronously replicated. Exceptions include genes subject to X inactivation, imprinted genes and the autosomal randomly monoallelically expressed genes we have analyzed (starting with our studies of odorant receptor genes and extending to immunoglobulin, T cell receptor and interleukin genes). Asynchronous replication is established early in development and is found in various cell types irrespective of transcription. Examining four mouse autosome pairs, we have recently shown that every cell has randomly chosen either the maternal or paternal copy of each given autosome pair, such that alleles of randomly monoallelically expressed genes scattered across the chosen chromosome are earlier replicating than the alleles on the homologous chromosome. Additionally, different chromosomes are not coordinated with one another. Therefore, our data indicate that the maternal and paternal copies of each autosome pair are rendered non-equivalent in individual mouse cells, a process that contributes to cellular diversity through its link to monoallelic transcription. Our data suggest that chromosome pair non-equivalence, rather than being limited to X-inactivation, is a fundamental property of mouse chromosomes. Following on our findings, I describe a series of experiments to further define mechanisms controlling genomewide regulation of monoallelically expressed genes. We propose to: 1. Establish that the observation of an autosomal analog of X-inactivation we have made in mice extends to human cells. 2. Examine the effects of various types of aneuploidies of one or more autosomes or portions thereof on the allele specific replication timing of autosomal genes. 3. Explore other epigenetic changes that may be involved in the allele-specific replication timing of autosomal genes. These studies will explore the novel, fundamental property of autosomes that we have discovered and will set the stage for exploring the role of this level of genome-wide gene regulation on genes relevant to human disease.
|Effective start/end date||1/08/03 → 31/07/07|
- National Institute of General Medical Sciences: $389,500.00
- National Institute of General Medical Sciences: $1,406,500.00
- National Institute of General Medical Sciences: $122,500.00
- National Institute of General Medical Sciences: $358,750.00
- National Institute of General Medical Sciences: $146,250.00
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