Abstract: Cell cycle variants are used during development to increase DNA content as a means to generate large cells or to permit localized changes in gene copy number. We term the latter differential DNA replication and have exploited its ubiquitous presence in differentiated tissues in Drosophila to decipher the developmental control of origin firing and fork progression. We find that both constitutive genome architecture and tissue specificity impact the distribution of replication origins. Replication fork progression can exhibit both tissue and region-specific properties. These developmental examples of differential DNA replication have provided powerful models for common chromosome fragile sites in humans and the events that can lead to genome instability in cancer cells. Increased cellular DNA content is a strategy to increase cell size. In the Drosophila nervous system, increased ploidy permits a subtype of glia to attain sufficient size to envelop the underlying neuronal mass to make the blood-brain barrier. Interestingly, distribution of this genomic DNA into multiple nuclei rather than a single nucleus within each cell is essential for glia function.
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