复杂性状遗传CC小鼠信息资源及研究应用

复杂性状遗传CC小鼠(CC小鼠)由不同遗传背景的小鼠品系杂交后,近交培育而成,用于研究人类复杂性状疾病和疾病的遗传差异。CC小鼠能体现不同小鼠亚种的遗传差异,其单核苷酸多态性是传统近交系小鼠的四倍。CC小鼠在生命科学与医学研究领域的应用越来越广泛。本文通过信息检索等方式对CC小鼠相关信息资源进行梳理,阐述了CC小鼠的起源、数据库、应用工具,以及研究领域等,以推动CC小鼠资源在中国得到广泛应用。     

复杂性状遗传CC小鼠与精准医学研究

生物组学技术在生物学、医学上的转化应用,为精准的个体化预防、诊断、治疗提供了关键性的技术体系,精准医学模式应运而生。实验动物学研究是疾病发病机制研究转化到临床不可或缺的手段。为应对目前严重危害人类疾病的复杂性、多样性特点,2002年国际复杂性状联盟(Complex Trait Consortium,CTC)倡议研发建立新的小鼠遗传资源库;通过不同纯系小鼠品系间的杂交创建小鼠复杂性状遗传资源库(Collaborative Cross mice,CC小鼠)。随着原始亲本小鼠(founder)选定、杂交品系的繁殖,CC小鼠在检测小鼠表型、疾病易感性、疾病发生发展及预后与遗传因素的关系方面进行了系列的尝试。文中将就CC小鼠在疾病发生发展及药物评价个体化研究中的应用做一简要介绍。     

复杂性状遗传CC小鼠——肿瘤研究新平台

癌症是由于机体细胞失去正常调控过度增殖而引发的一系列复杂性状疾病的统称,其本质上是一种基因疾病。用于传统肿瘤小鼠模型的重组近交(RI)品系由于只起源于两个近交祖系,因此规模小且等位基因多样性较少,在统计功效上存在局限性。复杂性状遗传(Collaborative Cross mice,CC)小鼠是由来自八个原始种系近交产生的数百种基因型不同的小鼠品系,能够体现不同小鼠亚种的遗传学变异,具有高遗传多样性,大种群规模等重要特征。它可以模拟人类复杂性状疾病中不同人群对病因或治疗方法个体易感性的差异,为促进复杂性状疾病易感基因筛查、基因功能发现等方面的研究提供了一个更好的研究工具与信息平台。本文就CC小鼠在医学应用中的研究现状、挑战性与局限性、以及其在肿瘤研究中的应用前景进行综述。     

代谢病相关的遗传工程小鼠模型

糖尿病及肥胖症等代谢性疾病已成为影响人类健康的主要疾病,属于多基因所致的代谢综合征,遗传模式复杂多样,至今仍所知甚少.理想的实验动物模型是我们深入了解代谢病病因、遗传及环境因素的必要工具,并且可以用来研究验证新的治疗药物.近年来,已经获得了大量的遗传工程动物模型,包括转基因、基因敲除模型等遗传工程动物,对于代谢性疾病的研究意义重大.本文主要介绍近年来应用较多的糖尿病及肥胖相关的遗传工程小鼠模型遗传特征及应用.     

小鼠ld基因的研究概况

小鼠是人类了解最全面、应用最广泛的实验动物，作为生命科学的重点研究对象，在揭示生命自然规律，研究人类疾病等诸多方面，一直起着重要的作用。     

小鼠的遗传分析技术及疾病模型

小鼠作为人类理想的疾病生物模型，不仅同人类具有生理相似性，而且为建立人类疾病模型提供了大量的遗传资源.“人类基因组和小鼠基因组计划”完成后，转基因动物、基因剔除和基因剔入、大规模突变、特异位点检测系统等一些新技术的出现，提高了克隆新易感基因和建立人类疾病小鼠模型的能力、本文对一些与小鼠疾病模发展有关的最新技术进行了总结。     

后基因组时代的基因工程小鼠

基因工程小鼠是当今生命科学中集成度最高的综合性研究体系之一，在认识“基因－蛋白质－生命现象”、制备人类疾病研究的实验动物模型，以及新药开发的评价体系等领域中具有重要作用。随着生命科学中功能基因组学的兴起和模式生物时代的到来，使得生物医药研究对基因工程小鼠的需求日趋增加，同时也促使基因工程小鼠技术体系得到了快速的发展。然而，在基因工程小鼠的产生中，仍存在着一些问题。它们的解决，则需加强一些与基因工程小鼠直接相关的基础问题和有潜在应用价值的基础问题的研究。     

结核病易感性的研究进展

大量的遗传学研究表明,结核病是多基因和环境因素共同作用的结果。近年来,结核病易感基因及其单核苷酸多态性(SNP)位点研究成为热点,但与易感性有确切关联的基因和SNP报道较少,并且某些易感基因有种族、人群、地域分布的差异,不同种群或地区的局部研究得到的研究结论常不一致,甚至相反,因此,需要进一步寻找能广泛适用的、有确切关联的易感基因。鉴于此,需要在具备基因多样性的实验动物中进行初筛,然后在动物或人群中验证。协同杂交(Collaborative Cross,CC)小鼠具有遗传多样性并且有清晰的背景基因数据库,可为结核易感性研究提供新的工具。本综述总结已报道的结核易感基因及其SNP的研究进展,展望CC小鼠在此研究的应用和重要意义。     

小鼠模型与人类疾病

小鼠是人类疾病理想的动物模型,不仅因为小鼠在生理上与人类极为相似而且小鼠的遗传资源非常丰富,其大量的传变异可作为研究人类的借鉴。另外,高分辨率的小鼠遗传及物理连锁图谱已经建成,小鼠基因组的测序工作不久即将完成,而且维修小鼠基因组的技术（包括建立转基因小鼠,基因敲除,以及改建小鼠染色体的技术）也已具备,分析复杂遗传病的方法也相继建立……。这些进展加速了对小鼠疾病基因位点的鉴定与克隆,同时也促进了新模型的建立,从而使得小鼠成为人类疾病动物模型的首选。小鼠传学分析的技术与资源,将简要介绍用于建立人类疾病的动物模型的基本技术与方法,以及现有的小鼠传资源,在以后各部分中,将列举涉及多种人类疾病的100多个小鼠模型,其中大多数的模型的变异,在小鼠与患者的表型极为相似;因而有助于人们理解人类疾病及寻找有效的预防,治疗方法。     

糖尿病肾病小鼠模型的研究现状

糖尿病肾病（diabetic nephropathy,DN）已成为导致终末期肾病的主要原因之一。小鼠是研究人类疾病最常用的实验动物优势明显。目前常用的DN小鼠模型难以完全模拟人类DN病变,限制了DN发病机制和治疗措施的进展。近年来应用基因工程技术和杂交技术建立了一些新的DN小鼠模型,其中部分模型能较好地模拟人类DN的典型病变。本文总结常见DN小鼠模型特点的基础上,对新建立的DN小鼠模型疾病表现、肾病特点及应用进行了分析,从而有助于DN发病机制的深入认识及DN研究中动物模型的合理选择。     

The Collaborative Cross mouse genetic reference population designed for dissecting complex traits

Complex traits are multifactorial traits controlled by polygenic host factors. These trait-related phenotypic characteristics and performance including body weight, blood chemistry, immune cell profiles, as well host susceptibility to infectious and chronic diseases. In recent years, tremendous efforts were invested aiming to map the host genetic factors attribute to these traits and subsequently clone the gene/s underlying these loci. In parallel to human studies, a number of mouse models and approaches were developed aimed to enhance the mapping process and the gene cloning. These include of using resources such as F2, backcross, advanced intercross lines, outbred populations, consomic, congenic and recombinant inbred lines (RIL). The constraints of these approaches were the limited resolution mapping of genomic regions of the quantitative trait loci (QTL) associated with the trait of interests, and the limited genetic diversity observed in the parental founders. To overcome these limitations, a new genetically highly diverse recombinant inbred lines of mouse population was established, namely the Collaborative Cross (CC), created from full reciprocal mating of 8 divergent strains of mice:A/J, C57BL/6J, 129S1/SvImJ, NOD/LtJ, NZO/HiLtJ, CAST/Ei, PWK/PhJ, and WSB/EiJ. By intercrossing these eight founders to generate the different CC lines, the genetic makeup of the newly developed resource is completely different from the eight parental lines, and will show heterosis, which subsequently will response differently comparing with their original founders. Finally, our results suggest that it is not essential to defining the phenotypic response of the eight parental lines, prior of assessing the CC lines, because it is believed that genetic interaction of the new genetic makeup of the new lines will reveal new phenotypic response, which completely different from the parental lines.In this report, we present to the community the power of the CC for dissecting variety of complex traits including host susceptibility to infectious and chronic diseases as well body performance traits. Based on our results from a variety of studies, we recommend to the community, that the best strategy of using this population is to aim of phenotyping about 50 and more of CC lines, with limited number of biological replicates (3-4 mice per line), and subsequently using the publicly available high dense genotype information of the CC lines as well the sequence database of the eight founders, it will be possible performing QTL mapping to a unprecedented precision genomic regions less than 1 MB, subsequently lead to identify potential strong candidate genes. These achievements are believed cannot be obtained with any other currently available mouse resource populations.     

基因工程大鼠研究进展

相对小鼠而言,大鼠在生理、行为、代谢等方面更接近人类。近年随着基因工程大鼠技术的开发,大鼠开始回归于生命科学实验和医药研究,基因工程大鼠的研究成为实验动物科学的热点。目前适用于大鼠基因工程的技术各有优缺点。本文对大鼠转基因技术,转座子技术,ZFN锌指酶技术,TALENs技术和基于胚胎干细胞的基因打靶技术的研究进展做了比较。     

复杂性状遗传CC小鼠在传染病领域的应用及研究进展

动物模型是传染病防控研究体系中的重要支撑环节,起到连接实验室基础科研和临床诊疗的桥梁作用。小鼠是目前最被广泛使用的传染病动物模型,然而,免疫系统完整的成熟小鼠很多情况下对某些传染病病原并不易感。近年来,开发临床病例表征与人类更接近的协同杂交(Collaborative Cross,CC)小鼠,又称复杂性状遗传小鼠资源是目前的研究热点和建立疾病动物模型的另一切入口。本文将对目前使用CC小鼠感染传染病病原(包括病毒、细菌、真菌等)后呈现出表型多样性的研究报道做一综述,以期为进一步研究CC小鼠对不同传染病的易感性,丰富我国传染病动物模型资源库,为应对各种重大及新发突发传染病及临床的精细化诊疗提供有价值的参考数据。并在此基础上,提出一系列有关CC小鼠资源目前亟待解决的关键科学技术问题,同时对未来在传染病领域的应用作一展望,以作抛砖引玉之用。     

The genetic reference population “Collaborative Cross”is a powerful resource for genetic discoveries and understanding complex genetic traits

The Collaborative Cross(CC) is a powerful genetic resource with a wide range of applications in medical research. It is a multiparental genetic reference population, composed of 200 recombinant inbred mouse strains. It was designed to be a resource for rapid mapping of genes that mediate complex traits. The CC has been produced following an intense breeding program that had taken over ten years to complete. It is now becoming available to the research community. While advances in human genetic technologies over the last decade have been substantial, the CC provides the ability to make discoveries not possible with other methods or resources. It can be applied to any subject that can be measured or modelled in the mouse. Here, we discuss a range of applications for which the CC can be used, with examples taken from the early characterization of this powerful resource.     

Gene-engineered models for genetic manipulation and functional analysis of the cardiovascular system in mice

Cardiovascular disease remains a key issue in healthcare. During the last decade, transgenic and gene-targeted mouse technology has provided invaluable insights into cardiovascular molecular biology. Given the similarities between the mouse and human genomes, this study proposes that information experimentally derived using genetically manipulated mice can contribute significantly to the understanding of human cardiovascular pathophysiology. We first introduced the basic principles and methods of genetic manipulation, such as the breeding background in mice and the factors of construct design. Secondly, we reviewed the analyses related to genetic manipulation of the cardiovascular system from embryonic to adult mice. In conclusion, the gene-engineered mouse model is one of the most important tools developed in recent basic and clinical research.