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  Identification, functional characterization and in vivo mouse CRISPR transgene modeling of novel human genome wide association variants for metabolic disease/ageing


   College of Medicine and Veterinary Medicine

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  Dr P Joshi, Prof N Morton  No more applications being accepted  Funded PhD Project (European/UK Students Only)

About the Project

Background
Advancing age is the greatest risk factor driving the metabolic dysregulation underpinning diabetes, cardiovascular disease and cancers. However, the molecular basis of this relationship is poorly understood. Identification of genes and genetic risk factors interlinking longevity, fat mass/distribution and cellular metabolism will help to advance our understanding of the ageing process. The Wilson/Joshi group have led genome wide association (GWA) meta-analysis to reveal the impact of homozygosity on complex traits (Joshi, PK, et al. and Wilson JF Nature 2015) and have already established an association between lifespan and two DNA variants in apoE alleles previously associated with chronic disease [Hypercholesterolame and Alzheimers; Joshi et al., Nature Communications acceptedin revision] emphasizing the interconnectedness of ageing and metabolic processes. The studentship will extend successful GWA and deep-phenotyping (e.g. accurate determination of fat distribution and parent life history traits), using computation/statistical genetics methods to discover novel human DNA variants linked to fat distribution and blood pressure in the unique population isolates of Orkney/Shetland (Schraut et al., manuscript in preparation). The use of population isolates enable alleles rare in the general population to rise to detectable levels in isolated populations.

An integrated approach to understanding ageing/metabolic disease risk: We are currently investigating the molecular basis of the lead adiposity/blood pressure variants, situated in a chromosome 4 gene intron, on promoter/enhancer function with the leading functional genomics group of Bickmore (Williamson et al., Genes & Development 2014) and the student will have the opportunity to extend this analysis to novel hits they discover in the project. The student will then contribute to CRISPR genome-editing to generate in vivo mouse models of the genes/variants with the leading-edge Wood laboratory (Wood AJ et al., Science 2011). Completion of the gene-to-function story will involve determining the metabolic impact of editing the identified candidate genes using “gold-standard” mouse metabolic phenotyping techniques with the Morton group (Morton et al., Nature Medicine accepted Feb 2016) in collaboration with the expertise of the Selman group in mammalian ageing and metabolism (Selman et al. Science, 2009). This powerful integrated training approach will take the student from identification of new variants/genes through to the understanding of their molecular and physiological mechanisms and illumination of potential new therapeutic targets for metabolic disease and ageing.

Aims and Training outcomes
This project will train the student in 3 critical areas relevant to precision medicine. 1. Bioinformatic analysis of large-scale human genetics datasets. 2. Functional genomics of the association intervals using bioinformatics and in vitro approaches (3D-FISH, chromosome conformation capture technologies) with rapid development of new CRISPR-targeted mouse models of the novel variants that they discover. 3. Cutting-edge phenotypic assessment, initially training on mature projects within the supervisors laboratories (unique candidates already discovered above). Together, this studentship project will provide a broad, highly dynamic and unique set of skills that will be highly competitive in the burgeoning genomics discovery era.

Application
You can apply here: http://www.gla.ac.uk/research/opportunities/howtoapplyforaresearchdegree/
Within the application, at the programme of study search field option, please select ‘MRC DTP in Precision Medicine’.

Please note that, in step 6 within the online application process, you are asked to detail supervisor/project title information. Please ensure that you clearly detail this information from the information provided within this abstract advert. Within the research area text box area, you can also add further details if necessary.

Please ensure that all of the following supporting documents are uploaded at point of application:
• CV/Resume
• Degree certificate (if you have graduated prior to 1 July 2016)
• Language test (if relevant)
• Passport
• Personal statement
• Reference 1 (should be from an academic who has a knowledge of your academic ability from your most recent study/programme)
• Reference 2 (should be from an academic who has a knowledge of your academic ability)
• Transcript

This is a joint programme between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

Enquiries
The supervisors of the project invite informal enquiries from interested applicants:
Prof Nik Morton: [Email Address Removed]
Dr Peter Joshi: [Email Address Removed]

Funding Notes

Start date:
September/October 2016

Qualifications criteria:
Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or soon will obtain, a first or upper-second class UK honours degree or equivalent non-UK qualifications, in an appropriate science/technology area.

Residence criteria:
The MRC DTP in Precision Medicine grant provides tuition fees and stipend of £14,296 (RCUK rate 2016/17) for UK and *EU nationals that meet all required eligibility criteria.

(*must have been resident in the UK for three years prior to commencing studentship)

Full qualifications and residence eligibility details are available here: http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/

General enquiries regarding programme/application procedure: [Email Address Removed]

References

1. Directional dominance on stature and cognition in diverse human populations. Joshi, P, et al., and Wilson JF Nature. 2015 Jul 23;523(7561):459-62. doi: 10.1038/nature14618.
2. Spatial genome organization: contrasting views from chromosome conformation capture and fluorescence in situ hybridization.Williamson I, Berlivet S, Eskeland R, Boyle S, Illingworth RS, Paquette D, Dostie J, Bickmore WA. Genes Dev. 2014 28:2778-91. doi: 10.1101/gad.251694.114. PMID: 25512564
3. The MS is Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ. Science. 2009 7;334(6052):39.
4. Targeted genome editing across species using ZFNs and TALENs. Wood AJ1, Lo TW, Zeitler B, Pickle CS, Ralston EJ, Lee AH, Amora R, Miller JC, Leung E, Meng X, Zhang L, Rebar EJ, Gregory PD, Urnov FD, Meyer BJ. Science. 2011 Jul 15;333(6040):307. doi: 10.1126/science.1207773.
5. Morton, N.M et al., Genetic identification of an adipocyte expressed anti-diabetic target in mice selected for resistance to diet-induced obesity. Nature Medicine manuscript accepted Feb 2016.

Where will I study?