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

新型人类基因组代谢关联变体的鉴定、功能表征和体内小鼠 CRISPR 转基因模型

• 批准号: 1805065
• 金额: --
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1805065
• 关键词: Identification; functional; characterization; vivo; mouse

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.

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小组已经领导了全基因组关联（GWA）荟萃分析，以揭示纯合性对复杂性状的影响（Joshi等人，2015年）。该奖学金将扩展成功的GWAS和深度表型（例如脂肪分布的准确测定），使用计算/统计遗传学方法发现与奥克尼/设得兰群岛独特人群分离株中脂肪分布和血压相关的新型人类DNA变异。该方法先前被用于鉴定和研究位于4号染色体基因内含子中的前导肥胖变体的分子基础，其与Bickmore的领先功能基因组学小组一起对启动子/增强子功能进行鉴定和研究（威廉姆森等人，2014年）。学生将有机会将这种分析扩展到他们发现的新命中，然后有助于CRISPR/Cas9基因组编辑，以利用领先的Wood实验室生成基因/变体的体内小鼠模型（Wood et al.，2011年）。完成基因到功能的故事将涉及使用莫顿小组的“金标准”小鼠代谢表型分析技术来确定编辑所鉴定的候选基因的代谢影响（莫顿等人，2016）与Selman小组的专业知识合作（Selman等人，2009）在哺乳动物衰老和代谢中的作用。这种强大的综合培训方法将带领学生从识别新的变异/基因，到了解其分子和生理机制，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学相关的三个关键领域。1.大规模人类遗传学芯片的生物信息学分析.使用生物信息学和体外方法（3D-FISH，染色体构象捕获技术）的关联间隔的功能基因组学，快速开发新的CRISPR靶向小鼠模型的新变体，他们发现3。尖端的表型评估（最初在成熟项目上进行培训）总之，这个学生项目将提供一套广泛，高度动态和独特的技能，在新兴的基因组学发现时代将具有高度竞争力。参考文献：Joshi et al.，2015.不同人群中身高和认知的方向优势。威廉姆森等，2014.空间基因组组织：来自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等人，2009.核糖体蛋白S6激酶1信号调节哺乳动物寿命。科学。伍德等人，2011.使用ZFN和TALEN进行跨物种的靶向基因组编辑。Morton等人，2016.遗传学鉴定硫代硫酸盐硫转移酶作为脂肪细胞表达的抗糖尿病靶点在选择瘦小鼠。自然医学。

项目成果

The genetic underpinnings of obesity

• DOI: 10.1016/j.cophys.2019.10.008
• 发表时间: 2019-12
• 期刊: Current Opinion in Physiology
• 影响因子: 2.5
• 作者: K. Kentistou;James F. Wilson;P. Joshi;N. Morton

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

• DOI: 10.1038/s41467-017-00934-5
• 发表时间: 2017-10-13
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Joshi PK;Pirastu N;Kentistou KA;Fischer K;Hofer E;Schraut KE;Clark DW;Nutile T;Barnes CLK;Timmers PRHJ;Shen X;Gandin I;McDaid AF;Hansen TF;Gordon SD;Giulianini F;Boutin TS;Abdellaoui A;Zhao W;Medina-Gomez C;Bartz TM;Trompet S;Lange LA;Raffield L;van der Spek A;Galesloot TE;Proitsi P;Yanek LR;Bielak LF;Payton A;Murgia F;Concas MP;Biino G;Tajuddin SM;Seppälä I;Amin N;Boerwinkle E;Børglum AD;Campbell A;Demerath EW;Demuth I;Faul JD;Ford I;Gialluisi A;Gögele M;Graff M;Hingorani A;Hottenga JJ;Hougaard DM;Hurme MA;Ikram MA;Jylhä M;Kuh D;Ligthart L;Lill CM;Lindenberger U;Lumley T;Mägi R;Marques-Vidal P;Medland SE;Milani L;Nagy R;Ollier WER;Peyser PA;Pramstaller PP;Ridker PM;Rivadeneira F;Ruggiero D;Saba Y;Schmidt R;Schmidt H;Slagboom PE;Smith BH;Smith JA;Sotoodehnia N;Steinhagen-Thiessen E;van Rooij FJA;Verbeek AL;Vermeulen SH;Vollenweider P;Wang Y;Werge T;Whitfield JB;Zonderman AB;Lehtimäki T;Evans MK;Pirastu M;Fuchsberger C;Bertram L;Pendleton N;Kardia SLR;Ciullo M;Becker DM;Wong A;Psaty BM;van Duijn CM;Wilson JG;Jukema JW;Kiemeney L;Uitterlinden AG;Franceschini N;North KE;Weir DR;Metspalu A;Boomsma DI;Hayward C;Chasman D;Martin NG;Sattar N;Campbell H;Esko T;Kutalik Z;Wilson JF
• 通讯作者: Wilson JF

New alcohol-related genes suggest shared genetic mechanisms with neuropsychiatric disorders.

新的酒精相关基因表明与神经精神疾病有共同的遗传机制

• DOI: 10.1038/s41562-019-0653-z
• 发表时间: 2019-09
• 期刊: Nature human behaviour
• 影响因子: 29.9
• 作者: Evangelou E;Gao H;Chu C;Ntritsos G;Blakeley P;Butts AR;Pazoki R;Suzuki H;Koskeridis F;Yiorkas AM;Karaman I;Elliott J;Luo Q;Aeschbacher S;Bartz TM;Baumeister SE;Braund PS;Brown MR;Brody JA;Clarke TK;Dimou N;Faul JD;Homuth G;Jackson AU;Kentistou KA;Joshi PK;Lemaitre RN;Lind PA;Lyytikäinen LP;Mangino M;Milaneschi Y;Nelson CP;Nolte IM;Perälä MM;Polasek O;Porteous D;Ratliff SM;Smith JA;Stančáková A;Teumer A;Tuominen S;Thériault S;Vangipurapu J;Whitfield JB;Wood A;Yao J;Yu B;Zhao W;Arking DE;Auvinen J;Liu C;Männikkö M;Risch L;Rotter JI;Snieder H;Veijola J;Blakemore AI;Boehnke M;Campbell H;Conen D;Eriksson JG;Grabe HJ;Guo X;van der Harst P;Hartman CA;Hayward C;Heath AC;Jarvelin MR;Kähönen M;Kardia SLR;Kühne M;Kuusisto J;Laakso M;Lahti J;Lehtimäki T;McIntosh AM;Mohlke KL;Morrison AC;Martin NG;Oldehinkel AJ;Penninx BWJH;Psaty BM;Raitakari OT;Rudan I;Samani NJ;Scott LJ;Spector TD;Verweij N;Weir DR;Wilson JF;Levy D;Tzoulaki I;Bell JD;Matthews PM;Rothenfluh A;Desrivières S;Schumann G;Elliott P
• 通讯作者: Elliott P

Author Correction: New genetic signals for lung function highlight pathways and chronic obstructive pulmonary disease associations across multiple ancestries.

作者更正：肺功能的新遗传信号强调了跨多个祖先的途径和慢性阻塞性肺疾病的关联。

• DOI: 10.1038/s41588-019-0438-3
• 发表时间: 2019
• 期刊: Nature genetics
• 影响因子: 30.8
• 作者: Shrine N

Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

全基因组关联和功能研究确定了 46 个新的饮酒基因座，并提出了神经精神疾病的常见遗传机制

• DOI: 10.1101/453332
• 发表时间: 2018
• 作者: Evangelou E