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本和父本衍生拷贝以相当的水平同时表达，并在S期的相同部分复制。但是，也有例外情况，即两个副本中的一个未被表示，并且这两个副本被异步复制。这些基因包括X失活基因、印记基因和我们分析过的常染色体随机单等位基因表达基因（从气味受体基因开始，延伸到免疫球蛋白、T细胞受体和白细胞介素基因）。异步复制在发育早期建立，并在各种细胞类型中发现，而与转录无关。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个给定常染色体对的母本或父本拷贝，因此分散在所选染色体上的随机单等位基因表达基因的等位基因比同源染色体上的等位基因更早复制。此外，不同的染色体彼此不协调。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是不等价的，这是一个通过与单等位基因转录的联系而促进细胞多样性的过程。我们的数据表明，染色体对的不等价性，而不是仅限于X-失活，是小鼠染色体的一个基本属性。 根据我们的研究结果，我描述了一系列的实验，以进一步确定单等位基因表达基因的全基因组调控控制机制。我们建议： 1.确定我们在小鼠中观察到的X失活的常染色体类似物延伸到人类细胞。 2.检查一个或多个常染色体或其部分的各种类型的非整倍性对常染色体基因的等位基因特异性复制时间的影响。 3.探索其他表观遗传学变化，可能涉及等位基因特异性复制时间的常染色体基因。 这些研究将探索我们发现的常染色体的新的基本特性，并为探索这种全基因组基因调控水平对人类疾病相关基因的作用奠定基础。

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.