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

Metabolic disease is one of the most prominent public health concerns in Western populations and is associated with predisposition to Type 2 Diabetes, cardiovascular disease and various cancers. The Wilson/Joshi group have led genome wide association (GWA) meta-analysis to reveal the impact of homozygosity on complex traits (Joshi et al., 2015). The studentship will extend successful GWAS and deep-phenotyping (e.g. accurate determination of fat distribution), 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. The use of population isolates enables alleles rare in the general population to rise to detectable levels in isolated populations.
This approach was previously used to identify and investigate the molecular basis of lead adiposity variants, situated in a chromosome 4 gene intron, on promoter/enhancer function with the leading functional genomics group of Bickmore (Williamson et al., 2014). The student will have the opportunity to extend this analysis to novel hits they discover and then contribute to CRISPR/Cas9 genome-editing to generate in vivo mouse models of the genes/variants with the leading-edge Wood laboratory (Wood et al., 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., 2016) in collaboration with the expertise of the Selman group (Selman et al., 2009) in mammalian ageing and metabolism. 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.
Thus, this project encompasses three critical areas relevant to precision medicine.
1. Bioinformatics 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)
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.
References:
Joshi et al., 2015. Directional dominance on stature and cognition in diverse human
populations. Nature.
Williamson et al., 2014. Spatial genome organization: contrasting views from chromosome
conformation capture and fluorescence in situ hybridization. Genes & development.
Selman et al., 2009. Ribosomal protein S6 kinase 1 signaling regulates mammalian life
span. Science.
Wood et al., 2011. Targeted genome editing across species using ZFNs and TALENs. Science.
Morton et al., 2016. Genetic identification of thiosulfate sulfurtransferase as an adipocyte-
expressed antidiabetic target in mice selected for leanness. Nature medicine.