The goal of this project is to apply statistical physics and probability theory to the problem of DNA replication in living cells. The replication of DNA is one of the most important processes in all of biology. DNA encodes all the information that is passed on to the next generation of cells, and it must be rapidly and faithfully copied when the time comes for cells to divide. Dramatic advances in sequencing technology and microscopy in the last two decades have allowed unprecedented experimental access to the inner workings of cells. We now have quantitative measurements of the dynamics of DNA replication in populations and even in individual cells. This means that the approaches of physics and applied mathematics can be applied to the study of DNA replication, and can be used to gain better understanding and new insights on this crucial phenomenon.
The replication of DNA is executed by molecular machines called DNA polymerase, which travel along the DNA molecule as it replicates it. The DNA polymerases must be assembled from several molecules at the starting point of replication – specific locations on the DNA called replication origins. These precursor molecule move in the nucleus through Brownian motion, making this a stochastic process. Once assembled, they travel through the DNA, “unzipping” it into its component strands and performing the replication as it goes. Because the DNA polymerase is a molecular machine, it is subject to thermal fluctuations from the environment, which affects how it moves. To further complicate things, the DNA is a busy place: many processes are taking place in it at the same time, especially protein synthesis. So the DNA polymerases can collide with other molecules bound to DNA and get stuck for a while. For all those reasons, DNA replication is expected to be highly stochastic. However, most models assume that the DNA polymerases travel at constant speed on the DNA. We will formulate mathematical models taking the stochastic nature of the movement of DNA polymerases into account. We will create numerical simulations to test the predictions from our theory, and compare our results to experimental data available from collaborators. We will also examine the assembly of the DNA polymerases from its component molecules, and model its waiting-time statistics.
This project addresses some fundamental questions on the nature of DNA replication, and we expect it will have high impact in the field.
Candidates should have (or expect to achieve) a UK honours degree at 2.1 or above (or equivalent) in Physics, mathematics, computer science, or similar degree along with knowledge of statistical physics and stochastic processes and some experience with programming.
• Apply for Degree of Doctor of Philosophy in Physics
• State name of the lead supervisor as the Name of Proposed Supervisor
• State ‘Self-funded’ as Intended Source of Funding
• State the exact project title on the application form
When applying please ensure all required documents are attached:
• All degree certificates and transcripts (Undergraduate AND Postgraduate MSc-officially translated into English where necessary)
• Detailed CV
• Details of 2 academic referees
Informal inquiries can be made to Dr Alessandro Moura ([email protected]
) with a copy of your curriculum vitae and cover letter. All general enquiries should be directed to the Postgraduate Research School ([email protected]
Jens Karschau, J Julian Blow, Alessandro PS de Moura (2012). Optimal placement of origins for DNA replication, Phys Rev Lett 108, 058101.
R Retkute, CA Nieduszynski, A de Moura (2011). Dynamics of DNA replication in yeast, Phys Rev Lett 107, 068103.