Tools for Genetic and Genomic Studies in the Dog

描述(申请人提供)：狗(犬科动物)基因组学的最新发展使该物种迅速成为模式生物，在研究复杂的遗传疾病和与人类状况相关的特征方面具有重大优势。它在基因组学领域的迅速崛起得益于7.6倍的基因组序列、200多万个单核苷酸多态(SNPs)的鉴定，以及一个拥有超过125,000个基因座的商业SNP微阵列。这些发展集中在不同品种之间巨大的表型差异，最近通过品系育种建立了许多品种，产生了用于遗传分析的有利单倍型结构，与其他动物模型相比，与人类疾病的生理和解剖关系更大，以及良好的系谱记录。充分利用这一模型进行基因研究的主要障碍是随时可以获得与感兴趣的特征相关的足够数量的对照和受影响的动物。康奈尔大学动物医院(CUHA)每年收治15,000名犬类患者(5,000名新就诊)。我们建议从我们医院入院的精选纯种犬中创建一个DNA库，准确地诊断出患有复杂疾病和具有强烈生物医学兴趣的特征。保守估计，我们现有的样本每年将增加约2,000个DNA样本，每年多达400个病例和对照的子集将接受高密度SNP基因分型。最初，我们将定位特定犬种中主人导向的攻击性、杆状锥体营养不良、肝脏微血管发育不良和肉芽肿性(溃疡性)结肠炎的基因座。我们将前瞻性地积累相同特定品种对照的表型数据。将对8岁以上的犬进行标准表型筛查，这些犬属于同一品种，并在本院确诊为12种最常见疾病。我们将鼓励犬类遗传图谱社区在费用分担的基础上提交对他们的病例和对照进行SNP基因分型的请求。康奈尔医学遗传档案馆将购买与此赠款申请支持的相同数量的测绘阵列。未来的图谱研究将集中在在高资质的外部顾问的建议下，在我们医院最常入院的犬种中的复杂疾病。SNP基因型和伴随的表型将被上传到加州大学圣克鲁斯分校(UCSC)基因组生物信息学镜像，并移植到原始的UCSC网站。我们将帮助减轻科学家重复收集对照样本的需要，我们将提供SNP基因型，以便以最低成本进行硅胶分析。通过将大量良好的表型样本与SNP基因型别相结合，该资源将促进复杂特征的遗传分析，使广大科学家能够获得犬只模型，并使狗成为生物医学研究中不可或缺的元素。

DESCRIPTION (provided by applicant): Recent developments in dog (Canis familiaris) genomics have catapulted this species to the status of a model organism, with major advantages for the study of complex genetic diseases and traits relevant to the human condition. Its rapid rise in genomics was fueled by a 7.6X genome sequence, the identification of over 2 million single nucleotide polymorphisms (SNPs), and a commercial SNP microarray with over 125,000 loci. These developments converge with the enormous phenotypic variation between different breeds, the recent establishment of many breeds by line breeding that has yielded an advantageous haplotype structure for genetic analyses, greater physiologic and anatomic relationship to human diseases than other animal models, and excellent pedigree records. The main barrier to fully exploit this model for genetic studies is ready access to sufficient numbers of control and affected animals relevant to the traits of interest. The Cornell University Hospital for Animals (CUHA) admits - 15,000 canine patients (5,000 new visits) each year. We propose to create a DNA repository from selected pure-breed dogs admitted to our hospital accurately diagnosed with complex diseases and traits of strong biomedical interest. A conservative estimate is that approximately 2,000 DNA samples per year will be added to our existing collection, and a subset of up to 400 cases and controls per year will be subjected to high-density SNP genotyping. Initially, we will map loci for owner-directed aggression, rod-cone dystrophy, hepatic microvascular dysplasia, and granulomatous (ulcerative) colitis in specific breeds of dog. We will prospectively accumulate phenotypic data for the same specific breed controls. A standard phenotype screen will be performed on dogs over 8 years of age belonging to the same breeds admitted with the 12 most frequently diagnosed diseases in our hospital. We will encourage the canine genetic mapping community to submit requests for SNP genotyping of their cases and controls, on a cost-sharing basis. The Cornell Medical Genetic Archive will purchase an equal number of mapping arrays as supported by this grant application. Future mapping studies will concentrate on complex diseases of dogs among those breeds most frequently admitted to our hospital under the advice of highly qualified, external consultants. The SNP genotypes and accompanying phenotypes will be uploaded to the University of California Santa Cruz (UCSC) Genome Bioinformatics mirror and ported to the original UCSC site. We will help alleviate the need for scientists to repetitively collect control samples and we will provide SNP genotypes to allow in silico analyses at minimum cost. By combining a large collection of well phenotyped samples with SNP genotypes, this resource will facilitate the genetic analysis of complex traits, make the canine model accessible to a wide cadre of scientists, and empower the dog as an indispensable element in biomedical research.