Investigating Spatial Determinants of DNA Replication Timing (360G-Wellcome-203727_Z_16_A)

Complete and error-free replication of the genome is necessary for the normal development and health of all organisms. However, the sheer scale of the genome necessitates precise regulation of replication: in a human cell, 3 billion bases are replicated in about 8 hours, with replication initiating from between 12,000 and 250,000 origins spread across 23 chromosome pairs (1). Interestingly, not all of these origins fire in any given S phase and of those that do fire, not all fire at the same time. In fact, the replication timing profiles of a range of model organisms have been shown to follow precise temporal orders specific to cell type and differentiation status (2). Deviations from this timing regimen can manifest in a range of consequences including chromosomal aberrations and increased mutational load (3). While a range of factors correlating to the observed replication timing profiles have been found, the composite set of known factors still does not fully recapitulate the observed nuances of replication timing. I hope to study how spatial organization of the genome impacts replication timing, with the goal of better understanding how replication proceeds to be better able to understand how it goes awry in disease such as cancer.