An Autosomal Analog of X-Inactivation

描述（由申请人提供）：在二倍体真核生物中，通常假设每个基因的母系和父系衍生副本以相当的水平同时表达，并在S期的同一部分进行复制。但是，也有例外情况，即未表示两个副本中的一个，并且这两个副本是异步复制的。例外情况包括受X失活影响的基因、印迹基因和我们分析的常染色体随机单等位基因表达基因（从我们对气味受体基因的研究开始，扩展到免疫球蛋白、T细胞受体和白细胞介素基因）。异步复制是在发育早期建立的，并且在各种细胞类型中发现，与转录无关。通过对四对小鼠常染色体的研究，我们最近发现，每个细胞都随机选择了每对常染色体的母系或父系拷贝，这样，随机单等位基因表达的等位基因分散在所选择的染色体上，比同源染色体上的等位基因更早复制。此外，不同的染色体不能相互协调。因此，我们的数据表明，每个常染色体对的母本和父本拷贝在单个小鼠细胞中呈现不相等，这一过程通过其与单等位基因转录的联系有助于细胞多样性。我们的数据表明，染色体对不相等，而不是局限于x失活，是小鼠染色体的基本特性。

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.