An Autosomal Analog of X-Inactivation

描述(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来源的拷贝在可比较的水平上同时表达，并在S时期的同一部分被复制。但是，也有例外情况，即两个副本中的一个没有表示，并且两个副本是异步复制的。例外包括X失活基因、印迹基因和我们分析的常染色体随机单等位基因(从我们对气味受体基因的研究开始，延伸到免疫球蛋白、T细胞受体和白细胞介素类基因)。异步化复制是在发育早期建立的，存在于不同类型的细胞中，与转录无关。研究了四对小鼠常染色体，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，这样散布在所选染色体上的随机单等位基因的等位基因比同源染色体上的等位基因复制得更早。此外，不同的染色体之间并不协调。因此，我们的数据表明，在单个小鼠细胞中，每个常染色体对的母本和父本的副本是不等同的，这一过程通过其与单等位基因转录的链接而促进了细胞多样性。我们的数据表明，染色体对不对等，而不是仅限于X-失活，是小鼠染色体的基本属性。 根据我们的发现，我描述了一系列实验，以进一步确定控制单等位基因表达的全基因组调控的机制。我们建议： 1.确定我们在小鼠身上观察到的X失活的常染色体类似物延伸到了人类细胞。 2.检测一个或多个常染色体或其部分的各种类型的非整倍体对常染色体基因的等位基因特异性复制时机的影响。 3.探索可能与常染色体基因的等位基因特异性复制时间有关的其他表观遗传学变化。 这些研究将探索我们已经发现的常染色体的新的基本性质，并将为探索这种水平的全基因组基因调控对与人类疾病相关的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.