Comprehensive Characterization of Canine Genomic Structural Diversity

描述(由申请人提供)： 项目概述家犬狼疮已成为分析表型多样性遗传基础的一个强大的模型系统。基因组工具与狗独特的品种结构相结合，使超过100个遗传区域与形态、行为和疾病表型联系在一起，其中许多涉及与人类健康相关的基因和表型。在过去的五年里，对人类的研究已经确定拷贝数和结构变异是导致疾病易感性的重要突变类型。在狗身上，使用微阵列的研究已经确定了1000多个拷贝数变异的位置，但这些研究的分辨率很低，仅限于检测大型事件，无法检测反转录元件插入，并且对倒置等平衡事件视而不见。到目前为止，在狗和其他模式物种中，CNV研究主要集中在数量不多的样本(&lt；100)，没有详细的表型信息。我们建议通过三个具体的目标来极大地扩展我们对狗CNV的分布、生物学基础和表型影响的理解，这些目的旨在(1)在41只狗的不同小组中定义结构变异单倍型的断点序列，(2)识别拳击手衍生的参考基因组组合中缺失的多态犬类基因组序列，以及(3)使用来自4000个表型个体的阵列强度和基因数据来评估常见和罕见拷贝数变异的频率。这将是第一次在非人类哺乳动物物种中进行这样的研究，并将使人们能够对潜在的基因组稳定性的突变过程有独特的见解。此外，这项研究将直接有助于未来和正在进行的使用基于阵列的基因分型绘制狗的医学相关表型图的努力，加强这些旨在识别和了解人类疾病背后的途径的努力。

DESCRIPTION (provided by applicant): Project Summary The dog, Canis lupus familiaris, has emerged as a powerful model system for analyzing the genetic basis of phenotypic diversity. Genomic tools coupled with the unique breed structure of dogs have permitted the association of over one hundred genetic regions with morphometric, behavioral, and disease phenotypes, many of which involve genes and phenotypes relevant to human health. During the past five years, studies in humans have identified copy-number and structural variation as important mutation types underlying disease susceptibility. In dogs, studies using microarrays have identified over 1000 sites of copy-number variation, but these studies are of poor resolution, have been limited to detecting large events, are unable to detect retroelement insertions, and are blind to balanced events such as inversions. In dogs and other model species, CNV studies to date have focused on modest numbers of samples (< 100) without detailed phenotype information. We propose to greatly extend our understanding of the distribution, biological basis, and phenotypic impact of dog CNVs through three specific aims designed to (1) define the breakpoint sequence of structurally variant haplotypes in a diverse panel of 41 dogs, (2) identify polymorphic canine genome sequences that are absent from the boxer-derived reference genome assembly, and (3) assess the frequency of common and rare copy-number variants using array intensity and genotype data from 4000 phenotyped individuals. This will be the first such study in a non-human mammalian species and will enable unique insights into the mutational processes underlying genomic stability. Furthermore, this research will directly contribute to future and ongoing effort to map medically relevant phenotypes in dogs using array-based genotyping, strengthening these efforts aimed at identifying and understanding pathways that underlie human disease.