Replication Timing: Evolution, Nuclear Organization and Relevance for Human Disease

Abstract

DNA replication in eukaryotes is multifaceted, dynamic and highly organised. In contrast to bacterial cells, which replicate from single origins of replication, complex eukaryote genomes replicate from thousands of origins of replication. Although we know that the timing of replication depends on the chromatin environment, the function and evolution of mechanisms controlling replication timing are unclear. Many studies in species ranging from yeast to humans have demonstrated how replication timing depends on proximity to certain sequences such as telomeres and centromeres (Ferguson and Fangman, 1992; Friedman et al., 1996; Heun et al., 2001), chromatin status (euchromatin and heterochromatin) and is linked to gene function and expression (housekeeping genes versus tissue specific genes and monoallelically expressed genes) (Hiratani and Gilbert, 2009; Hiratani et al., 2009). Replication timing has been linked to fundamental epigenetic regulatory mechanisms including genomic imprinting (Kitsberg et al., 1993; Knoll et al., 1994), X chromosome inactivation (Gilbert, 2002; Takagi et al., 1982; Wutz and Jaenisch, 2000), interchromosomal interactions (Ryba et al. 2010) and is increasingly recognised to be important in human disease (DePamphilis, 2006). This chapter integrates established knowledge with recent scientific breakthroughs, using genome-wide approaches linking different aspects of epigenetic control with replication timing, to provide a state-of-the-art overview and perspective for future work in this area of research. Despite detailed knowledge on replication timing in a select number of model organisms (e.g. yeast, drosophila, mouse) we are only beginning to understand how replication timing evolved in relation to other epigenetic mechanisms (e.g. genomic imprinting, X inactivation, and long-range chromatin interaction). The evolution of these epigenetic mechanisms will be presented together with novel ideas about how cytological and genome-wide approaches and methodologies can be combined to provide a comprehensive picture of spatial and temporal organization, the evolution of replication timing in eukaryotic genomes, and their relevance in human disease.