ResearchMy group works on the causes and consequences of genome change. We are particularly focused on mechanisms by which genetic rearrangements are stimulated by the environment, and how this impacts gene expression both transiently and heritably. We aim to discover and the extent and importance of regulated genome alteration, particularly as genomes change during ageing.
The potential for genome change is rarely considered; although we know that carefully orchestrated DNA rearrangements can be performed by cells, notably in the generation of antibody diversity, this is seen as exceptional.
Nonetheless, all eukaryotic genomes contain regions of variable copy number in areas such as telomeres, centromeres and the ribosomal DNA. Rearrangements in these areas are tightly regulated, as might be expected for such functionally critical chromosomal regions, and are clearly controlled by the cell.
More surprisingly, we have recently shown that the action of these regulatory pathways is not restricted to specialised regions, and that many normal protein coding genes may be subject to regulated genetic change, providing a pathway by which cells can alter particular regions of their genome in response to the environment.
It is becoming clear that genetic changes, notably variations in gene copy number, frequently occur not just in tumours but also in normal cells of higher eukaryotes. This can have major medical implications as copy number variations are thought to contribute to a plethora of genetic disorders, while cancer cells and eukaryotic parasites can gain drug resistance though changes in gene copy number.
Changing the copy number of a gene could increase the amount of protein produced by that gene, but could also lead to recognition by cellular defence mechanisms that shut down genes of high copy number, and currently the contribution of these two effects is poorly understood.
As we age our cells accumulate genetic changes and so diverge at differing rates, both from the inherited genome and from each other. We suggest that these variations will have major effects on gene regulation and as such, the accumulation of copy number changes in different tissues may well form an important component of the ageing process. We are researching how these changes arise, and what effects they have, and are very interested in the potential for regulation of age-linked genome change.
Current research topics in the lab include the control of recombination by chromatin structure, non-coding RNAs and signalling pathways, and the regulation of gene expression and chromatin structure during ageing.