The Donnelly research group is primarily interested in studying human genetic variation and its role in human disease. It is challenging to distinguish those variants that contribute to susceptibility from the much larger set of variants that do not. Our research group develops sensitive statistical techniques for this purpose.
The ability to measure genetic variants on a genomic scale in large numbers of sick and healthy individuals, first through genotyping up to a million markers, and now through sequencing of entire genomes, has revolutionised the study of the genetic basis of common human diseases. The resulting data sets are large and complex, putting a premium on the development and application of sophisticated and efficient statistical methods for their analysis. Indeed, with the acceleration in technological development, the need for analytical tools has become a major bottleneck in exploiting genomic technologies.
I have been fortunate to lead some of the largest human genetics studies ever undertaken, across over 25 diseases and conditions: the Wellcome Trust Case Control Consortia (WTCCC and WTCCC2). Moving forward, my group is developing and applying novel methodologies in several DNA-sequence-based disease studies. We have also used genetic data to learn about the demographic histories of modern populations. In collaboration with Professor Sir Walter Bodmer of the Department of Oncology and other colleagues, we have collected a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised population that can be used as a resource by the research community, as well as providing a fine-scale genetic information on the British population.
In collaboration with Simon Myers and Gil McVean, we are continuing our work to understand the mechanisms underlying recombination, and its regulation, following our successful identification first of a DNA sequence motif associated with recombination hotspots in humans (the first known in any species) and then of the key gene involved in hotspot localisation. We are employing a combination of statistical, genomic, and functional approaches.
We are collaborating with UK Biobank on genotype analysis of 500,000 volunteers who have already contributed physical measurements and information about their health and lifestyle. The data will be returned to UK Biobank so that approved researchers can study the of relevance of genetic differences, together with other health and lifestyle factors (such as diet and activity levels) to the incidence of many different diseases.
Genomic technologies offer unprecedented opportunities to study the bacterial pathogens responsible for many infectious diseases. In collaboration with colleagues in Oxford, we are obtaining entire DNA sequences of carefully sampled bacterial isolates, to better understand the biology of the pathogens, the genetic basis and spread of virulence and antibiotic resistance, and the mechanisms of transmission between infected individuals.
International Multiple Sclerosis Genetics Consortium and Wellcome Trust Case Control Consortium 2. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–9
Myers S et al. Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science. 2010;327:876–9
The Wellcome Trust Case Control Consortium. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature. 2010; 464:713–720