Sunday, 26 January 2014

Three jobs @UCL

With clinical colleagues at UCL, we are looking for motivated applicants to take on three job opportunities with a significant computational/statistical/bioinformatics component. I am involved in each of these projects but the main lead is clinical.Two are at the postdoctoral level and one at the PhD. The closest deadline is the PhD application (January 31st, which is this coming Friday), the two postdocs deadlines are further in time and about to be advertised. Do not hesitate to contact either myself or one of the other listed investigators directly if interested.

Three year postdoc: Transcriptome analysis in blood and iPS cells of retinitis pigmentosa (RP) patients
Funding: RP fighting blindness
Investigators/Collaborators; Andrew Webster, Tony Moore, Michel Michealides, Shomi Bhattacharya (inherited retinal disorders), Pete Coffey (induced pluripotential stem cell technology) and myself
This project has the strongest mol bio/wet lab component but the applicant should either have or will gain familiarity with the analysis of RNA sequencing data. It will investigates retinitis pigmentosa (RP), a Mendelian disorder that causes retinal degeneration and blindness. It is due to many specific genes that affect the development and/or maintenance of rod photoreceptors, the most abundant light-transducing cell in the human retina. Although many genes have already been identified, discovering the biological link between mutant or absent protein on the one hand, and specific dysfunction and death of rod photoreceptors on the other, is challenging. Without understanding the detailed molecular pathology, novel treatments will not be possible.

The project benefits from a large resource of such patients and families managed at Moorfields Eye Hospital and investigates the pathophysiology of those affected by mutations in splicing-factors. These comprise a significant proportion of affected patients including RP11, RP9, RP13 and RP18. The underlying genes encode proteins that make up the spliceosome, and are expressed in all eukaryotic cells. One enigmatic feature of these disorders is the fact that heterozygous mutation (they are all autosomal dominant disorders) causes specific problems with the retina and not, as far as is known, any other organ or cell-type. One further interesting feature of these disorders is the manifestation of variability, and sometimes non-penetrance in gene-carriers. By investigating this further, ameliorating factors might be identified.

The project plans to address these questions by the thorough analysis of the transcriptome of affected gene-carriers compared to those gene-carriers without disease and controls (ethinically matched non-carriers). We intend to use RNA-Seq experiments to explore this comprehensively, in collaboration with Dr Vincent Plagnol and colleagues at UCL Genetics Institute. Secondly, we intend to generate iPS cells from patients’ skin biopsies and thereafter retinal pigment epithelial cells and photoreceptor progenitor cells to explore their transcriptomes and phenotypes. This will be under the supervision of Professor Pete Coffey and team at UCL Institute of Ophthalmology.

This represents an opportunity to understand eukaryotic splicing and its aberration in human retinal disease. It will require a willingness to generate and work with RNA-Seq data, understand human inherited disease and be able to develop iPS and derived cells in cell culture. Hence the successful candidate will gain a wide experience in molecular and cell biology as well as bioinformatics.

Three year postdoc: Genetics of epilepsy
Investigator: Sanjay Sisodiya, UCL Institute of Neurology and myself
Funding: Wellcome Trust, European Union, MRC

Epilepsy refers a complex and heterogeneous set of disorders, and its etiology remains hard to elucidate. Sanjay Sisodiya at the UCL Institute of Neurology (IoN) leads a successful research program that investigates the genetic basis of these diseases and how this genetic basis affects response to treatments. Cases that are part of the study are very deeply phenotyped, including novel experimental techniques and extensive long term follow-up. High throughput sequence data (a lot of exome sequences, > 200 whole genome sequences) are being generated and are now becoming available. We are looking for an postdoctoral researcher to work on these data. There will be plenty of scope to develop new bioinformatics/statistical methods. The size of the dataset continues to increase and a lot of additional information about these patients is also available, which provides an opportunity to tackle pharmacogenomics questions.

Four year PhD studentship: System biology for graft versus host disease (GVHD)
Investigators: Ronjon Chakraverty, Clare Bennett (UCL Cancer Institute) and myself
Funding: Gordon Piller PhD studentship, Leukaemia and Lymphoma research
Deadline: January 31

This project uses a systems biology approach and mouse models to investigate the basis of graft-vs-host disease, i.e. the process of donor immune cells attacking the host organs, a severe complication following bone marrow transplant. As part of our research program, we are tracking clonal or polyclonal donor T cell responses across multiple sites in pre-clinical models of GVHD and evaluating transcriptional profiles and/or T cell receptor (TCR) sequences of purified cell populations. The student will use computational methods in a ‘dry lab’ environment (in collaboration with V Plagnol) to assess these microarray and TCR sequence data and to evaluate the extent to which GVHD is driven by TCR repertoire-dependent or independent factors. Systematic methods will be used to compare differentially expressed genes in our models with (1) multiple chipSeq maps that provide a genome-wide view of transcription factor binding sites and (2) extensive, publicly available gene expression datasets for human and murine T cells in other inflammatory conditions. These approaches will be used to identify novel regulatory or downstream effector pathways implicated in GVHD. Extensive cross talk between ‘dry’ and ‘wet’ lab researchers in our LLR program will permit further experimentation or data analysis as new hypotheses are formulated and tested.