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

代谢性疾病是西方人群中最突出的公共卫生问题之一，与2型糖尿病、心血管疾病和各种癌症的易感性有关。Wilson/Joshi团队领导了基因组全关联（GWA）荟萃分析，揭示了纯合性对复杂性状的影响（Joshi等人，2015）。该奖学金将扩展成功的GWAS和深度表型（例如精确确定脂肪分布），使用计算/统计遗传学方法在奥克尼/设得兰群岛独特的种群分离中发现与脂肪分布和血压相关的新型人类DNA变异。群体分离物的使用使一般人群中罕见的等位基因在孤立人群中上升到可检测的水平。这种方法之前被Bickmore领先的功能基因组学小组用于识别和研究铅肥胖变异的分子基础，这些变异位于4号染色体基因内含子中，具有启动子/增强子功能（Williamson等，2014）。学生将有机会将此分析扩展到他们发现的新hit，然后与领先的Wood实验室一起为CRISPR/Cas9基因组编辑做出贡献，以生成基因/变体的体内小鼠模型（Wood et al., 2011）。完成基因到功能的故事将涉及与Morton小组（Morton等人，2016）以及Selman小组（Selman等人，2009）在哺乳动物衰老和代谢方面的专业知识合作，使用“金标准”小鼠代谢表型技术，确定编辑已确定的候选基因的代谢影响。这种强大的综合训练方法将带领学生从识别新的变异/基因到理解它们的分子和生理机制，并阐明代谢疾病和衰老的潜在新治疗靶点。因此，该项目包括与精准医疗相关的三个关键领域。大规模人类遗传数据集的生物信息学分析。利用生物信息学和体外方法（3D-FISH，染色体构象捕获技术）对关联区间进行功能基因组学研究，并快速开发新的crispr靶向小鼠模型，以研究他们发现的新变体3。总之，这个学生项目将提供一个广泛的、高度动态的和独特的技能，这将在迅速发展的基因组学发现时代具有很强的竞争力。参考文献：Joshi等，2015。不同人群在身高和认知方面的定向优势。大自然。Williamson et al., 2014。空间基因组组织：从染色体构象捕获和荧光原位杂交的对比观点。基因与发育。Selman et al., 2009。核糖体蛋白S6激酶1信号调控哺乳动物寿命。科学。Wood et al., 2011。利用ZFNs和TALENs进行跨物种靶向基因组编辑。科学。Morton等人，2016。瘦小鼠脂肪细胞表达的抗糖尿病靶点硫代硫酸盐硫转移酶的遗传鉴定。自然医学。

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 discover3. 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 humanpopulations. Nature.Williamson et al., 2014. Spatial genome organization: contrasting views from chromosomeconformation capture and fluorescence in situ hybridization. Genes & development.Selman et al., 2009. Ribosomal protein S6 kinase 1 signaling regulates mammalian lifespan. 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.