Identifying Genome Wide SINE Retrotransposons Contributing to Dog Size Variation

识别导致狗体型变化的全基因组正弦反转录转座子

• 批准号: 8032110
• 负责人: Nathan B Sutter
• 金额: $ 26.95万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-03 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8032110
• 关键词: Apert syndrome; Blindness; Body Size; Breeding; Canis familiaris; Centronuclear myopathy; Chromosome Mapping; Cloning; Complex; Complex Genetic Trait; DNA; Data; Degenerative polyarthritis; Disease; Dwarfism; Evolution; Explosion; Gene Expression; Genes; Genetic; Genetic Structures; Genetic Variation; Genomics; Genotype; Goals; Growth; Growth and Development function; Hand; Health; Hereditary Disease; Human; Human Genome; Knowledge; Lead; Limb structure; Malignant Neoplasms; Mammals; Methods; Modeling; Morphology; Mutagenesis; Narcolepsy; Nature; Obesity; Outcome; Pattern; Phylogeny; Population; Public Health; Recording of previous events; Research; Resources; Retinitis Pigmentosa; Retrotransposition; Retrotransposon; Shapes; Short Interspersed Nucleotide Elements; Spliced Genes; Structure; Testing; Thick; Variant; Work; base; bone; burden of illness; cranium; deafness; dog genome; functional genomics; gene discovery; genome-wide; improved; innovation; malignant breast neoplasm; man; novel; skeletal; tool; trait

DESCRIPTION (provided by applicant): The population structure of the world's 400 dog breeds is a powerful tool for dissecting the genetics of complex traits like skeletal size. The dog acquired skeletal size diversity early in its history and on a very short evolutionary timescale of a few thousand years. But the nature of the functional genomic sequences that made this possible is not known. This lack of knowledge is an important problem for the field because without it we cannot fully exploit the dog's genomic and population structure to maximize power in mapping genes for disease and morphology. Heritable diseases of both man and dog are caused by retrotransposon insertions that disrupt genes. While retrotransposons segregate for insertion and non-insertion at many loci in the dog genome, this is rare in the human genome. Our long-term goal is to understand the mechanisms for rapid trait diversification during dog evolution. The objective here is to identify the pattern of short interspersed element (SINE) retrotransposon insertions in the dog genome and identify SINEs contributing to size variation. Our central hypothesis is that an explosion of SINE retrotranspositions during domestication provided functional sequence variation that enabled rapid diversification of traits under selection, such as body size. The rationale for the proposed research is that the dog's long history of intense selection under domestication, population structure and naturally occurring genetic diseases make the species a vital resource for understanding complex traits in man. Therefore, an improved understanding of retrotransposition within the dog genome will increase the dog's value as a model for human health, growth and development. With supportive preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify the genome-wide pattern of SINE retrotranspositions in the dog; and 2) Identify SINE insertions contributing to body size differences. A method for massively parallel sequencing genomic DNA that flanks SINEs has been developed and established as feasible in the applicant's hands. SINEs discovered in small and giant purebred dogs will be tested for association with size and genotyped in a large panel of purebred dogs to identify loci contributing to size variation. SINEs that disrupt gene expression and splicing will also be identified and a SINE-based breed phylogeny will be built. The approach is innovative because it utilizes a novel cloning method to characterize an underappreciated functional sequence variant in a non-traditional but increasingly valuable mammal model. This contribution is significant because it is the first step along a research trajectory expected to further unlock the intrinsic value of the domestic dog's evolution, population structure, size variation and genetic disease burden in an effort to better understand complex traits in man. PUBLIC HEALTH RELEVANCE: The proposed research is relevant to public health because a genetic understanding of growth and body size in the dog will serve as a model for the genetics of complex traits in man. Furthermore, the discovery and characterization of thousands of retrotransposons in the dog genome will ultimately lead to an improved understanding of how they cause heritable diseases in man.

描述（由申请人提供）：世界上 400 个犬种的种群结构是剖析骨骼大小等复杂性状遗传学的有力工具。狗在其历史的早期就在几千年的非常短的进化时间范围内获得了骨骼尺寸的多样性。但使这成为可能的功能基因组序列的性质尚不清楚。这种知识的缺乏是该领域的一个重要问题，因为没有它，我们就无法充分利用狗的基因组和种群结构，以最大限度地提高绘制疾病和形态基因图谱的能力。人类和狗的遗传性疾病都是由逆转录转座子插入破坏基因引起的。虽然逆转录转座子在狗基因组的许多位点上分离插入和非插入，但这在人类基因组中很少见。我们的长期目标是了解狗进化过程中特征快速多样化的机制。这里的目标是确定狗基因组中短散布元件 (SINE) 逆转录转座子插入的模式，并确定导致大小变异的 SINE。我们的中心假设是，驯化过程中正弦逆转录转座的激增提供了功能性序列变异，使得选择下的性状（例如体型）能够快速多样化。这项研究的基本原理是，狗在驯化、种群结构和自然发生的遗传疾病下的严格选择的悠久历史使该物种成为了解人类复杂性状的重要资源。因此，更好地了解狗基因组内的逆转录转座将增加狗作为人类健康、生长和发育模型的价值。有了支持性的初步数据，这一假设将通过追求两个具体目标来检验：1）确定狗中 SINE 逆转录转座的全基因组模式； 2) 识别导致身体尺寸差异的正弦插入。申请人手中已经开发并建立了一种用于对 SINE 侧翼的基因组 DNA 进行大规模并行测序的方法，并且该方法是可行的。在小型和巨型纯种狗中发现的 SINE 将在一大群纯种狗中进行与体型的关联测试，并进行基因分型，以确定导致体型变异的基因座。破坏基因表达和剪接的 SINE 也将被识别，并建立基于 SINE 的品种系统发育。该方法具有创新性，因为它利用一种新颖的克隆方法来表征非传统但越来越有价值的哺乳动物模型中未被充分认识的功能序列变体。这一贡献意义重大，因为这是研究轨迹的第一步，预计将进一步揭示家犬进化、种群结构、体型变异和遗传疾病负担的内在价值，以更好地了解人类的复杂特征。 公共健康相关性：拟议的研究与公共健康相关，因为对狗的生长和体型的遗传理解将作为人类复杂性状的遗传学模型。此外，狗基因组中数千个反转录转座子的发现和表征最终将导致人们更好地了解它们如何导致人类遗传性疾病。