DNA replication and genome evolution and stability.

All cells contain a complete copy of the organism's DNA, the genetic blueprint of life, packaged into discrete units called chromosomes. Since new cells need a copy of the genetic material, the chromosomes must be completely and accurately replicated before the cell can divide. Mistakes during DNA replication fuel evolution, but can also drive disease. This research aims to determine how cells ensure that the replication of each chromosome is completed accurately.

Problems during DNA replication may underlie or be diagnostic for some diseases. Problems can occur when the machinery that copies the DNA encounters an obstacle. This can cause the DNA replication machinery to slow or pause which in turn can give rise to duplications, the expansion/contraction of repeated sequences or even lead to breaks in both strands of the DNA. Therefore, although obstacles rarely cause a problem for DNA replication, when they do the consequences can be catastrophic for the cell.

Rare events, such as pausing of the replication machinery, can be difficult to detect, since most DNA replication is occurring normally. These rare, but serious events, present a ‘needle in a haystack’ problem for researchers. We have developed a high-throughput DNA sequencing technology that allows us to study the kinetics of DNA replication in vivo on single molecules. This technology allows us to rapidly search for the ‘needle in the haystack’ and identify rare, but serious, events such as the slowing down or pausing of the DNA replication machinery. This is important because a single DNA replication error on one chromosome in a single cell division can give rise to disease.