Tools for Genetic and Genomic Studies in the Dog

描述（由申请人提供）：犬（Canis familiaris）基因组学的最新发展使该物种成为一种模式生物，在研究与人类状况相关的复杂遗传疾病和性状方面具有主要优势。它在基因组学领域的迅速崛起得益于7.6X基因组序列，超过200万个单核苷酸多态性（SNP）的鉴定，以及拥有超过12.5万个位点的商业SNP微阵列。这些发展与不同品种之间巨大的表型差异相结合，最近通过系育种建立的许多品种已经产生了有利的单倍型结构，用于遗传分析，与其他动物模型相比，与人类疾病有更大的生理和解剖关系，以及优秀的系谱记录。充分利用这一模型进行遗传研究的主要障碍是准备好获得足够数量的与感兴趣的性状相关的对照和受影响动物。康奈尔大学动物医院（CUHA）每年收治15000名犬类病人（新就诊人数5000人）。我们建议建立一个DNA库，从入选的纯种犬中挑选出准确诊断出复杂疾病和具有强烈生物医学兴趣的特征的犬。保守估计，每年将有大约2000个DNA样本添加到我们现有的收集中，每年将有多达400个病例和对照进行高密度SNP基因分型。首先，我们将绘制特定犬种的主人定向攻击、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。对我院12种最常诊断疾病的8岁以上同品种犬进行标准表型筛查。我们将鼓励犬类基因图谱社区在费用分摊的基础上提交其病例和对照的SNP基因分型请求。康奈尔医学遗传档案馆将购买等量的测绘阵列，以支持这项拨款申请。未来的测绘研究将集中于在高素质的外部顾问的建议下，在我们医院最经常收治的品种中狗的复杂疾病。SNP基因型和伴随表型将被上传到加州大学圣克鲁兹分校（UCSC）基因组生物信息学镜像，并移植到UCSC原始站点。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计算机分析。通过将大量表型良好的样本与SNP基因型相结合，该资源将促进复杂性状的遗传分析，使犬类模型可供广泛的科学家使用，并使犬类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.