Chromosome inverted fusions, dicentrics and genome instability

描述（由申请人提供）：基因组重排是细胞染色体的变化，可引起病理。细胞中常见的基因组重排，由细胞复制错误引起。其中一种被称为大规模重排，对细胞特别有害；它可以改变某些基因的数量，可以使基因突变，还可以产生不稳定的染色体，这些染色体会不断地重新排列。在人类中，很明显，大规模的重排确实会引起重大的病理，最著名的例子是费城染色体，其中Chr22和Ch9的部分融合，形成基因融合，导致白血病。最近对癌症基因组的深度测序揭示了一系列令人困惑的大规模变化；在一些染色体中，似乎已经爆炸并随机地拼凑在一起，在其他染色体链中，染色体链连接在一起。如前所述，大规模重排也会形成固有的不稳定染色体，包括含有两个着丝粒的双中心染色体，因此是不稳定的。一种特殊的重排在胰腺癌细胞中出现频率很高。这被称为反向折叠，染色体与自身融合形成双中心。为什么我们对反向反转特别感兴趣？我们已经开发了一个芽殖酵母染色体不稳定系统，使我们能够研究大规模的重排。我们现在已经确定了一种折叠后反转型染色体变化（我们称之为反向融合），在酵母中，确实形成了双中心。这种融合似乎经常发生在酵母基因组中，尽管我们还不知道在哪里或有多频繁。我们研究了这种酵母反向融合/折叠反向形成的机制，并提出了一个我们可以测试的模型。在这个提议中，我们将鉴定酵母中融合形成双中心的序列。这将提供关于融合在人类基因组中有多常见的信息。我们将研究融合是如何发生的，这对于了解胰腺细胞中融合是如何发生的以及如何在正常人类细胞中避免融合是很重要的。最后，我们将在分裂酵母和人类细胞中建立遗传系统来研究折叠反转。这将使我们开始直接了解在胰腺癌中如何出现折叠反转类型的重排。

DESCRIPTION (provided by applicant): Genome rearrangements are changes to cells chromosomes that can cause pathology. Genome rearrangements common in cells, and arise due to errors in cell duplication. One type, called a large scale rearrangement, is particularly deleterious to a cell; it can change the number of certain genes, can mutate a gene, and can generate unstable chromosomes that continue to rearrange. In humans it is clear that large scale rearrangements indeed cause significant pathology, a most famous case being the Philadelphia Chromosome where parts of Chr22 and Ch9 fuse, forming a gene fusion that causes leukemia. Recent deep sequencing of cancer genomes reveals a bewildering array of large scale changes; in some chromosomes appear to have exploded and pieced back together randomly, in others there are chains of chromosomes joined together. As mentioned, large scale rearrangements also form inherently unstable chromosomes, including dicentrics that contain two centromeres and are thus unstable. One particular rearrangement arises at a high frequency in pancreatic cancer cells. It's called a fold back inversion, where a chromosome fuses with itself such that it should form a dicentric. Why are fold back inversions of particular interest to us? We have developed a budding yeast chromosome instability system allows us to study large scale rearrangements. We have now identified a fold back inversion type chromosome change (that we call an inverted fusion), in yeast, that indeed forms dicentrics. Such fusions appear to occur frequently in the yeast genome, though we do not yet know where or how frequently. We have studied the mechanism of how this yeast inverted fusion/fold back inversion forms, and propose a model we can test. In this proposal, we will identify sequences in yeast that fuse to form dicentrics. This will provide information on how common fusions may be in the human genome. We will study how fusions occur, important for knowing how fusions occur in pancreatic cells and how they are avoided in normal human cells. Finally, we will establish genetic systems in fission yeast and in human cells to study fold back inversions. This will allow us to begin to directly understand how foldback inversion types of rearrangements arise in pancreatic cancer.