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

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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.