Postgraduate research study
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PhD project: Physics of genome structure in disease

Project description

The genome is the genetic material of an organism. Consisting of DNA packaged up with proteins to form chromosomes, it contains the instruction set or genetic code which tells a cell how to grow and function. The genome must be copied when cells grow and divide, and must be accessed to read the code to produce proteins, the building blocks of the cell. In different types of cell and during different stages of development, different parts of the genetic code need to be accessed, i.e. different genes need to be switched on or off. The physical polymer structure of the chromosomes plays a major role in how this is regulated. We are interested in using computer simulations and methods from soft matter and statistical physics to understand this in healthy cells and disease.

Possible projects include:

  1. Developing a new model for chromatin structure where individual nucleosomes are represented. Chromatin is the composite material made up from DNA and proteins which forms the chromosomes. A nucleosome is a disk-like structure formed when DNA wraps around a bundle of proteins called histones; a chain of nucleosomes forms a chromatin fibre. Though the crystal structure of the nucleosome is known, how a chain of nucleosomes folds up, and how that affects the larger scale polymer structure is still unclear. Recent developments in experimental methods have provided new data on the positions of nucleosomes. In this project you will use coarse grained molecular dynamics simulations and develop a new model for chromatin which makes use of this data. You will build on existing methods from soft matter, statistical and polymer physics. You will then use the model to understand how changes in nucleosome positions, e.g. when genes are activated, change the larger scale structure. There will be opportunities to work with experimental data from collaborators who are studying chromatin structures in disease.
  2. Using polymer simulations to understand how genome rearrangements lead to mis-regulation of genes in genetic disorders and cancer.  You will use and further develop an existing simulation model which can predict chromosome loops which drive gene expression. Using data from collaborators at the University of Newcastle, you will use the simulations to predict how genome rearrangements found in cancer change this looping structure. Genome rearrangements can occur, for example, when breaks in the chromosomes are incorrectly repaired, and regions which are usually far apart in the genome are brought together. This results in changes to the chromatin polymer structure; you will use non-equilibrium polymer models to simulate this process. The simulation results will help us understand how common rearrangements give rise to disease, and will help our experimental collaborators with development of possible treatments.

Some relevant references:

  1. Daniel Rico, Daniel Kent, Aneta Mikulasova, Nefeli Karataraki, Rolando Berlinguer-Palmini, Brian A. Walker, Biola M. Javierre, Lisa J. Russell, Chris A. Brackley "High-resolution simulations of chromatin folding at genomic rearrangements in malignant B-cells provide mechanistic insights on proto-oncogene deregulation" bioRxiv 2021.03.12.434963
  2. O. Wiese, D. Marenduzzo, and C. A. Brackley "Nucleosome positions alone determine micro-domains in yeast chromosomes" Proc. Natl. Acad. Sci. USA 116 17307-17315 (2019)
  3. A. Buckle, C. A. Brackley, S. Boyle, D. Marenduzzo and N. Gilbert "Polymer Simulations of Heteromorphic Chromatin Predict the 3-D Folding of Complex Genomic Loci" Molecular Cell 72 1-12 (2018)

Project supervisor

The project supervisor welcomes informal enquiries about this project.

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