Genetics, Epigenetics & Bioinformatics

Human molecular genetics|Most of the UK population has been exposed to Bovine Spongiform Encephalopathy (BSE, commonly known as mad cow disease) by eating contaminated food. The germ that causes BSE, called a prion, may infect humans, resulting in a fatal brain illness called variant Creutzfeldt-Jakob disease (vCJD). While there are few patients to date, we do not know how many might be infected with the disease and develop symptoms later. |vCJD has so far only affected one genetic subtype of individual, found in 40% of healthy people in the UK. Whether other genetic types will become affected, and if so whether they will have an illness like vCJD is unknown. It is clear that genes are important in controlling who will get vCJD. To study this we are using modern technologies to measure many hundreds of thousands of different genetic types, and compare these between groups of the healthy population and vCJD patients.|We are also developing and applying methods to extract, combine and make sense of the huge amount of genetic and other information which is generated by scientists working in the field of molecular biology and Prion research around the world.|Bioinformatics|We are developing and applying methods to extract, combine and make sense of the huge amount of data which is generated by scientists working in the field of molecular biology and Prion research around the world. This includes large sets of data generated by us in the Prion Unit, towards furthering our understanding of the underlying principles of Prion disease. We are able to do this through information technology and the use of fast computers, software programs for analysis and access to data via the internet.

The MRC Prion Unit Human Molecular Genetics of Prion and Related Dementias Programme investigates why some people, but not others, get prion diseases such as Creutzfeldt-Jakob disease (CJD). By comparing genetic differences between people who developed CJD and healthy people we hope to identify genes that influence why particular people are more susceptible to these diseases, and use this information to better estimate public health risks and to develop new tests and treatments. We also know that the fundamental processes involved in CJD, where one of the bodys own proteins becomes misshapen and then forms large clumps of material, are very relevant to other much commoner diseases such as Alzheimers Disease. ||Evidence in support of the involvement of non- PRNP genetic factors comes in part from work with laboratory inbred mouse strains, detailed in this groups section. A small number (~5) of quantitative trait loci (QTL) responsible for determining incubation time following intra-cerebral inoculation with prions have been mapped by the MRC Prion Unit and others using different crossing strategies and prion strains. The integration of unbiased genome-wide strategies in mouse and human prion disease will be an important in the success of both programs. Our discovery research utilises recently available genome-wide genotyping technologies. We have successfully conducted a pilot genome-wide association study with EA-Affymetrix 500K arrays (Mead et al. Lancet Neurology 2009). The necessary molecular genetic, bioinformatic, and statistical genetic expertise for genome-wide association study is either available in the Unit or through collaboration. Over the next few years we expect to develop our discovery genome-wide association research in larger patient cohorts using more advanced genotyping technologies, and focus on developing cellular and animal models to test the genes identified in our discovery research. It has become increasingly apparent that neurodegenerative diseases share fundamental mechanisms involving protein misfolding, including Alzheimers disease and Parkinsons disease. It is likely that genetic modifiers of prion pathogenesis may be of broader relevance to other protein misfolding diseases, and we intend to explore these possibilities.|One of the key goals of bioinfomatics in the Unit is to identity modifier genes, pathways and mechanisms controlling prion pathogenesis. The objective of this aspect of the programme is to use computational and statistical methods for the analysis and integration of these Unit based large-scale experiments (and also externally generated data sets) and their resulting data sets, which are large, inherently noisy and do not produce necessarily clear candidates.