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  • Jim Hughes, Thomas Milne, James Davies, Stephen Taylor

ABOUT THE RESEARCH

The Hughes group is interested in the basic mechanisms which control the activities of genes and how sequence changes in the regulatory non-coding portion of the genome alter gene expression and underlie common human diseases.  The sequences which codes for protein only represents ~2% of the human genome and this small fraction has been the focus of the majority of scientific scrutiny over the last 30 years.  However, work over the last decade and a half has shown that the vast majority of sequence changes that underlie most common human diseases, such as diabetes, cardiac, cancer, neurological and autoimmune diseases, lie in the non-coding rather than coding portion of the genome. The development of complex multicellular organisms is completely dependent on the exquisitely orchestrated expression of gene networks, as is our cells’ abilities to react to stimuli from our environment. It is therefore suspected and, in some cases, confirmed, that these changes in our non-coding genome alter the behaviour of embedded regulatory elements and so effect the “how” and “where” such genes are expressed, rather than the structure of the proteins themselves.

To understand the link between our genomes and our susceptibility to common diseases it is therefore imperative to understand both the mechanisms by which genes are normally regulated and how such sequence variation can alter the output of such regulatory circuits.  The interrogation of the non-coding genome and gene regulation are demanding questions and requires the application and development of cutting edge computational and molecular approaches.  The Hughes group in expert in both molecular and computational approaches developing novel molecular assays, such as Capture-C and novel computational machine learning approaches such as DeepC.  It is also expert in the use and analysis of a wide range of genomics methods (ATAC-seq, ChIP-seq, transcriptomics and Chromatin Conformation Capture (3C) methods) and is also leveraging them at the single cell level to map out regulatory landscapes in the non-coding genomes of complex cellular systems. 

Please see the Weatherall Institute for Molecular Medicine (WIMM) for information about applications for a DPhil in Medical Sciences with groups based in the WIMM.

 

TRAINING OPPORTUNITIES

DPhil opportunities exist for both purely computational research and for bench research.  The computational projects would suit a candidate with a strong computer science, mathematical or statistical background and will focus on using Deep Neural Network approaches to model regulatory function in the human genome. No formal biological background is required, and the candidate will be trained in the analysis and interpretation of genomics and epigenomics data.  The bench projects would suit a candidate with a biological background and the student will learn how to perform genomics methods such as ATAC-seq, ChIP-seq and RNA-seq, as well as specialist 3D genome 3C methods such as Capture-C, Tiled-C and Hi-C.   Other projects leverage large-scale synthetic biology and genome editing combined with genomics. The candidate will be trained in the bioinformatic analysis and integration of these datasets so that the student can independently perform and analyse their own data.

Students will be enrolled on the MRC WIMM DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

 

PUBLICATIONS

Schwessinger, R et al.  BioRXiv https://doi.org/10.1101/724005

Oudelaar, A et al Nature Communications https://www.nature.com/articles/s41467-020-16598-7

Oudelaar, A et al Nature Genetics https://www.nature.com/articles/s41588-018-0253-2

Chiariello, A et al Cell Reports https://doi.org/10.1016/j.celrep.2020.01.044

Schwessinger, R et al Genome Research https://doi.org/10.1101/gr.220202.117

 

Davies, J et al Nature Methods https://doi.org/10.1038/nmeth.3664