Does genome replication in Leishmania rely on origin-independent initiation?

任何生物体的生长和繁殖都依赖于其基因组的忠实传递——基因组是提供生命蓝图的遗传物质。基因从父母传递给后代需要遗传物质被复制，然后被分离。复制过程称为复制。在细胞生物中，基因组是由DNA构成的，其复制通常被描述为一个高度调控的过程，在这个过程中，特定蛋白质识别并结合基因组中的特定区域，即基因组复制开始的地方。在细菌中，基因组中只有一个起源，而更复杂的生物体，包括人类在内的真核生物，在构成其基因组的每条染色体中都有成百上千个起源。尽管教科书中对起源的描述对复制至关重要，但一些研究表明，当起源被移除，或当起源结合蛋白被删除或其功能受到干扰时，基因组复制就会发生。因此，一个关键问题是，一些细胞生物是否可以在不依赖起源的情况下正常复制它们的基因组。如果是这样，起源独立复制的描述将改变我们对基因组复制策略的进化和适应性的看法。在这个项目中，我们希望确定利什曼原虫，一种引起利什曼病的寄生虫，一种世界范围内的毁灭性疾病，是否可能是真核生物中基因组复制依赖于灵活的，独立于起源的复制起始事件的第一个例子，以及更有限的起源定义的复制。我们将追求尖端的遗传和全基因组分析，以验证我们对利什曼原虫染色体DNA复制的不寻常的双峰策略的预测，包括如何在基因组的非起源位点刺激复制。我们认为，利什曼原虫依赖于起源独立复制的假设解释了这种寄生虫及其近亲的已知倾向，即快速改变其基因组的遗传组成，这可能在未来导致针对它们引起的疾病的新疗法，并更好地了解它们的致病性和耐药性机制的发展。此外，我们的工作可能解释更广泛生物体的基因组变异，包括基因组重排导致疾病的地方，例如癌症和发育障碍。

The growth and propagation of any living organism is dependent on the faithful transmission of its genome - the genetic material that provides the blueprint for life. Transmission of the genome from parent to offspring requires that the genetic material is copied and then segregated. The copying process is referred to as replication. In cellular organisms, the genome is made of DNA and its replication is normally described as a highly regulated process in which specific proteins recognise and bind to specific regions in the genome, termed origins, where copying of the genome begins. In bacteria one origin is found in the genome, whereas more complex organisms, the eukaryotes, which include humans, possess hundreds or thousands of origins in each of the chromosomes that make up their genome. Despite this textbook description of origins being essential for replication, some studies have shown that genome replication can occur when origins are removed, or when the origin binding proteins are deleted or their function disturbed. A key question, then, is whether or not some cellular organisms might normally replicate their genomes without relying on origins. If so, the description of origin-independent replication would alter our view of the evolution and adaptability of genome replication strategies. In this project, we wish to determine if Leishmania, a parasite that causes leishmaniasis, a devastating disease worldwide, might be the first example of a eukaryotic organism in which genome copying relies on flexible, origin-independent replication initiation events, in addition to more limited origin-defined replication. We will pursue cutting-edge genetic and genome-wide analyses to test our prediction of an unusual, bimodal strategy for DNA replication in Leishmania chromosomes, including how replication might be stimulated at non-origin sites of the genome. We suggest that our hypothesis of Leishmania reliance on origin-independent replication explains the known propensity of this parasite, and its relatives, to rapidly vary the genetic composition of their genome, which might in the future lead to new therapies against the diseases they cause and to the better understanding of their pathogenicity and the development of resistance mechanisms to drugs. In addition, our work might explain genome variation in wider organisms, including where genome rearrangement leads to disease, for e.g. cancer, and developmental disorders.