A High Density Gene Map of the Canine Genome

描述(申请人提供)：到目前为止，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性基因的定位和克隆，这是通过使用Extreme的连锁图谱研究确定的，即“高风险家族”。这类家庭很少见，而且由于其规模较小，往往提供的遗传信息有限，特别是如果关键家庭成员已经死亡或没有生育后代的话。此外，人类种群结构的内在局限性，如较长的世代时间和异种繁殖，意味着具有弱渗透性、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定位。对于癌症这样的疾病尤其如此，在这些疾病中，大量的低渗透性等位基因被认为占了人群中相当大比例的疾病。我们之前假设，在绘制与人类疾病相关的基因图谱方面，家犬比其他系统有几个关键优势。明显的优势包括狗的大家庭规模，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有限基因异质性。在这笔赠款中，三个经验丰富和互动的小组将扩大他们正在进行的合作，以开发狗的位置克隆基础设施，从而建立家犬作为绘制癌症易感基因和其他常见疾病等位基因的模型系统的选择。此前，我们开发了犬1800标记的减数分裂连锁/辐射杂交(RH)图谱，该图谱由微卫星、EST和BAC末端组成，覆盖了超过95%的基因组。我们已经通过绘制包括犬肾癌和四种类型的视网膜变性在内的几种疾病的基因座图，展示了这些地图的实用性。在这项建议中，我们将通过以下方式为这些和其他狗感兴趣的疾病基因的定位克隆奠定基础：1)从10,000多个犬基因中鉴定适合进行RH定位的片段，从基因组研究所(TIGR)提供的1倍犬基因组序列中定位；2)使用新开发的高分辨率(10,000-rad)RH面板定位10,000个犬基因的片段；以及3)开发并使基因组学社区容易获得包含这些数据和当前正在生成的额外数据的犬RH图谱。

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.