Comprehensive Characterization of Canine Genomic Structural Diversity

犬基因组结构多样性的综合表征

• 批准号: 8417247
• 负责人: Adam R Boyko
• 金额: $ 30.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-05 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8417247
• 关键词: Architecture; Automobile Driving; Behavioral; Biological; Biological Models; Body Size; Breeding; Canis familiaris; Collection; Copy Number Polymorphism; Coupled; DNA Sequence Rearrangement; Data; Disease; Disease susceptibility; Dog Diseases; Electronics; Elements; Environment; Equilibrium; Etiology; Event; Evolution; Frequencies; Future; Genes; Genetic; Genetic Recombination; Genetic Variation; Genome; Genome Stability; Genomic Instability; Genomics; Genotype; Gray Wolf; Haplotypes; Health; Hereditary Disease; Hot Spot; Human; Individual; Knowledge; Link; Location; Longevity; Maps; Medical Records; Modeling; Mus; Mutation; Pathway interactions; Phenotype; Play; Process; Reading; Recurrence; Research; Research Personnel; Resolution; Retroelements; Retrotransposon; Role; Sampling; Scanning; Short Interspersed Nucleotide Elements; Site; Structure; Systems Analysis; Validation; Variant; base; blind; design; disease phenotype; disorder risk; dog genome; genome sequencing; homologous recombination; human disease; insertion/deletion mutation; insight; public health relevance; sample collection; screening; structural genomics; tool; trait

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.

描述（由申请人提供）： 狗，Canis lupus familiaris，已经成为分析表型多样性遗传基础的强大模型系统。基因组工具加上狗的独特品种结构，使超过100个遗传区域与形态，行为和疾病表型，其中许多涉及与人类健康相关的基因和表型的关联。 在过去的五年中，对人类的研究已经确定拷贝数和结构变异是疾病易感性的重要突变类型。在狗中，使用微阵列的研究已经确定了超过1000个拷贝数变异的位点，但是这些研究的分辨率很差，仅限于检测大事件，无法检测反转录元件插入，并且对平衡事件（如倒位）是盲目的。在狗和其他模型物种中，迄今为止的CNV研究集中在没有详细表型信息的适度数量的样本（< 100）上。 我们建议通过三个特定的目标来大大扩展我们对犬CNV的分布、生物学基础和表型影响的理解，这些目标设计为：（1）在41只犬的不同小组中定义结构变异单倍型的断点序列，（2）鉴定拳击手衍生的参考基因组组装中不存在的多态性犬基因组序列，和（3）使用来自4000个表型个体的阵列强度和基因型数据评估常见和罕见拷贝数变异的频率。这将是第一个在非人类哺乳动物物种中进行的此类研究，并将使人们能够对基因组稳定性背后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努力，利用基于阵列的基因分型来绘制犬的医学相关表型，加强这些努力，旨在识别和理解人类疾病的基础途径。