Genetic Architecture of the Mammalian (Canid) Skeleton

哺乳动物（犬科动物）骨骼的遗传结构

• 批准号: 7118238
• 负责人: KARL Gordon LARK
• 金额: $ 31.02万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7118238
• 关键词: animal population genetics; biopsy; dogs; gender difference; genetic markers; genetic regulation; genetically modified animals; genotype; laboratory mouse; linkage disequilibriums; morphology; nucleic acid repetitive sequence; phenotype; quantitative trait loci; single nucleotide polymorphism; skeletal system; tissue /cell culture

DESCRIPTION (provided by applicant): As its goal, this project seeks to decipher the genetic architecture underlying the mammalian skeletal system. We use a population of Portuguese Water (PW) Dogs, descended from a few founders and characterized by frequent inbreeding events. This unstructured pedigreed population is similar to human isolates such as the Hutterites or larger well documented populations such as the Mormons. Dogs are genotyped using microsatellite markers and phenotyped from five x-rays comprising the skull, fore- and hind limbs and pelvis. From this information it has been possible to identify QTLs (haplotypes of Quantitative Trait Loci) that inform the skeleton. During the first 2+ years of the project, we have used Principal Component Analysis to define groupings of skeletal metrics that represent functional trade-offs between adaptations for power or speed (e.g. skull vs. post cranial body, limb width vs. length, pelvis size vs. limb width) and have identified genetic loci that regulate these groupings. Loci also have been identified that regulate variation in the right vs. the left hip joints (bilateral asymmetry); and an interaction between QTLs affecting size has been identified that, in part, explains sexual dimorphism. In continuing this project we shall (i) complete the analysis of the canine genome; (ii) analyze several QTLs in detail; and (iii) attempt to transfer specific canine genetic information to the mouse, (i) Missing genotypic information (gaps in genome markers) will be supplied using the canine genomic sequence as a source of new markers to identify QTLs in the approximately 30% of the genome that remains to be analyzed, (ii) In a collaborative effort with Dr. Elaine Ostrander, four unlinked QTLs will be examined in detail that regulate: a) limb bone length vs. limb width; b) skull length vs. limb width; c) overall size; and d) size differences between males and females (sexual dimorphism). This detailed analysis will utilize the emerging sequence of the canine genome, analyzing each QTL haplotype with a high density of markers (SSR and then SNP) to pinpoint the informative region of sequence. Linkage disequilibrium analysis within the PWD population as well as between PW dogs and other breeds will be a powerful tool, (iii) Emerging murine transgenic technology suggests that it will be possible for canine genes to be transferred to, and function in, the mouse. In a collaborative effort with Dr. Capecchi, we shall carry out such a transfer.

描述（由申请人提供）：作为其目标，该项目试图破译哺乳动物骨骼系统的基础遗传结构。我们使用葡萄牙水（PW）狗的种群，来自一些创始人，其特征是经常发生近亲事件。这种非结构化的卵材化种群类似于人类分离株，例如hutter石或较大的有记录良好的人群，例如摩门教徒。使用微卫星标记物对狗进行基因分型，并通过五张X射线表型，其中包括头骨，前肢和后肢和骨盆。从这些信息可以识别QTL（定量性状基因座的单倍型），以告知骨骼。在该项目的前2年以上，我们使用主要成分分析来定义骨骼指标的分组，这些骨骼指标代表功能或速度适应之间的功能权衡（例如，颅骨与颅后身体，肢体宽度与长度，骨盆大小与肢体宽度）并确定了调节这些组的遗传位置。还已经确定了基因座调节右髋关节（双侧不对称）的调节变化；影响大小的QTL之间的相互作用已被确定，部分原因是性二态性。 在继续这个项目时，我们将（i）完成对犬类基因组的分析； （ii）详细分析几个QTL； （iii）尝试将特定的犬类遗传信息转移到鼠标中，（i）使用犬类基因组序列作为新标记的来源，将提供丢失的基因型信息（基因组标记中的空白），以识别大约30％的基因组中的QTL来识别基因组中的QTL，这些基因组仍将在尚未与Elaine of of the of the of the of of osere of的基因组中进行分析：肢体长度与肢体宽度； b）头骨长度与肢体宽度； c）整体尺寸； d）男性和女性之间的大小差异（性二态性）。这种详细的分析将利用犬基因组的新兴序列，以高密度标记（SSR，然后是SNP）分析每个QTL单倍型，以查明序列的信息区域。 PWD种群中的连锁不平衡分析以及PW犬与其他品种之间的连锁不平衡将是一种强大的工具，（iii）新兴的鼠转基因技术表明，将有可能将犬基因转移到小鼠中并发挥作用。通过与Capecchi博士的合作，我们将进行这样的转移。