A High Density Gene Map of the Canine Genome

描述（由申请人提供）：迄今为止，人类家族和人群中疾病易感基因的鉴定主要集中在常染色体显性高渗透基因的作图和克隆上，通过使用极端“高风险家族”的连锁作图研究确定。这样的家庭很少见，而且由于其规模小，通常提供的遗传信息有限，特别是如果主要家庭成员已经去世或没有生育后代。此外，人类种群结构的固有限制，如长世代时间和近亲繁殖，意味着渗透性弱的基因，产生可变表型，或与其他基因协同作用产生复杂表型的基因极难绘制。对于像癌症这样的疾病来说尤其如此，在这种疾病中，大量的低渗透等位基因被认为是造成人口中很大比例疾病的原因。我们先前假设，家养狗在绘制人类疾病相关基因图谱方面比其他系统有几个关键优势。明显的优势包括狗的家庭规模大，以及创始人效应和狭窄的种群瓶颈，这导致纯种狗常见疾病的基因座异质性有限。在这笔拨款中，三个经验丰富的互动小组将扩大他们正在进行的合作，开发狗的位置克隆基础设施，从而建立家犬作为癌症易感基因和其他常见疾病等位基因定位的选择模型系统。之前，我们开发了一个集成的1800个标记犬减数分裂连锁/辐射杂交（RH）图谱，由微卫星、est和bac端组成，覆盖了95%的基因组。我们已经通过绘制几种疾病的基因座，包括犬肾癌和四种类型的视网膜变性，证明了这些地图的实用性。在本提案中，我们将为定位克隆这些和其他狗感兴趣的疾病基因奠定基础：1)从基因组研究所（TIGR）提供的1x犬基因组序列中鉴定超过10,000个犬基因片段，适合RH定位；2)使用新开发的高分辨率（10,000 rad） RH面板绘制10,000个犬类基因片段；3)开发并向基因组学社区提供包含这些数据和目前正在生成的其他数据的犬RH地图。

DESCRIPTION (provided by applicant):The identification of disease susceptibility genes in human families and populations to date has focused on the mapping and cloning of autosomal dominant highly penetrant genes, identified by linkage mapping studies using extreme, "high risk families." Such families are rare and because of their small size often provide limited genetic information, particularly if key family members are deceased or have not produced offspring. In addition, inherent limitations in the structure of human populations, such as a long generation time and outbreeding mean that genes which are weakly penetrant, give rise to variable phenotypes, or act in concert with other genes to produce complex phenotypes are extremely difficult to map. This is particularly true for diseases like cancer, in which a multitude of low penetrant alleles are believed to account for a significant percentage of disease in the population.We hypothesized previously that the domestic dog offers several key advantages over other systems for mapping genes relevant to human disease. Obvious advantages include the large family size of dogs, as well as founder effects and narrow population bottlenecks that result in limited locus heterogeneity for common disorders among purebred dogs.In this grant, three experienced and interactive groups will expand their ongoing collaborations to develop the infrastructure for positional cloning in dogs, thus establishing the domestic dog as the model system of choice for mapping cancer susceptibility genes, as well as other common disease alleles. Previously we developed an integrated 1800 marker meiotic linkage/radiation hybrid (RH) map of the dog, composed of microsatellites, ESTs, and BAC-ends that spans over 95 percent of the genome. We have demonstrated the utility of these maps by mapping loci for several diseases, including canine renal cancer and four types of retinal degeneration. In this proposal we will set the stage for positional cloning of these and other disease genes of interest in the dog by 1) Identifying fragments from greater than 10,000 canine genes, suitable for RH mapping, from the 1x canine genome sequence being made available by The Institute for Genomic Research (TIGR); 2) Mapping fragments from 10,000 canine genes using a newly developed, high resolution (10,000-rad) RH panel; and 3) Developing and making readily available to the genomics community a canine RH map inclusive of these and additional data currently under generation.