Dr Colin Semple: Biomedical Systems Analysis
Regulatory Genomics in Evolution
Our group undertakes computational analyses of large-scale genomic, transcriptomic and genotyping datasets to investigate human disease and molecular evolution in mammals. Highlights have included exploratory, genome-wide studies of regulatory sequence evolution (Taylor et al, 2006) and of human chromosome structure and mutation rates (Prendergast et al, 2007). At the same time we have been active in studies of medical relevance, such as the reconstruction of regulatory networks in cancer (FANTOM Consortium, 2009).
- Professor Wendy Bickmore MRC Human Genetics Unit, Edinburgh, UK.
- Professor Malcolm Dunlop MRC Human Genetics Unit, Edinburgh, UK.
- Professor Yoshihide Hayashizaki Genome Science Centre, RIKEN, Yokohama, Japan.
- Professor Chris Haley, Roslin Institute and MRC Human Genetics Unit, Edinburgh, UK.
- Dr Martin Taylor MRC Human Genetics Unit, Edinburgh, UK
Current lab members involved in this work are:
- Dr Colin Semple - Head of Bioinformatics
- Dr Stuart Aitken - Bioinformatician
- Dr Philippe Gautier - Bioinformatician
- Mr Graeme Grimes - Bioinformatician
- Dr Vera Kaiser - Bioinformatician
- Dr Alison Meynert - Bioinformatician
- Sarah Baker - PhD student
- Zhenhua Hu - PhD student
- Ben Moore - PhD student
We have also been active in more focused work, examining the regulation and evolution of genes studied by human disease geneticists. These results have guided the subsequent work of experimental biologists.
We exploit large-scale datasets to study mammalian genome function and evolution.
Approach, Progress and Future Work
We aim to build on our past work and existing collaborations to examine regulatory genomics in evolution and disease at various levels:
(i) Chromatin structure in development and disease
We have examined the correlation between chromatin fiber structure and various evolutionary parameters such as mutation and selection across the human genome (Prendergast et al, 2007). We intend to extend this work to generate new insights into development and disease states with an epigenetic component, such as cancers.
(ii) Comparative epigenomics
Developments in high throughput sequencing have provided the first glimpses of conservation and divergence of the epigenomic landscape between species (Semple and Taylor, 2009), we are currently studying the dynamics of chromatin structure over evolutionary time.
(iii) Transcriptional regulation and molecular evolution
Our studies of the dynamics of mammalian promoter evolution concluded that primate regulatory sequences appeared to have suffered an unusual mutational spectrum (Carninci et al, 2006; Taylor et al, 2006). This work has generated new questions that we aim to address by studying patterns of mutation and selective constraint at higher resolution. In addition we are undertaking novel analyses of new datasets made available through our participation in an ongoing international consortium: the FANTOM Consortium (The FANTOM Consortium, 2009).
(iv) Prediction of causal variants in human disease
We have had a long-standing interest in prioritising genetic variants for meta-analyses of human disease (Turner et al, 2003) and in genome-wide association studies (Tenesa et al, 2008). Recent work has suggested several strategies to increase the success of such analyses.