Long-read assembly and annotation of rat genomes that are important models of complex genetic disease

大鼠基因组的长读组装和注释是复杂遗传疾病的重要模型

• 批准号: 10449388
• 负责人: PETER A DORIS
• 金额: $ 42.53万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-12 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449388
• 关键词: Addictive Behavior; Affect; Agriculture; Alternative Splicing; Amylases; Animal Model; Animals; Automated Annotation; Behavior; Behavioral; Behavioral Research; Biodiversity; Biological; Biological Process; Biology; Biomedical Research; Brain; Brain Diseases; Carbohydrates; Cardiovascular Physiology; Characteristics; Chromosomes; Communities; Complex; Data; Deposition; Development; Diet; Digestion; Disease; Disease model; Disease susceptibility; Distant; Drug Addiction; Elements; Ensure; Event; Evolution; Experimental Models; Funding; Gene Duplication; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Models; Genetic Variation; Genome; Genomic DNA; Genomics; Grain; Hi-C; Human; IGH@ gene cluster; Inbred BN Rats; Inbred Strains Rats; Inbreeding; Investigation; Knowledge; Laboratories; Libraries; Ligation; Link; Liquid substance; Long-Evans Rats; Manuals; Medical; Methods; Modeling; Molecular Conformation; Mus; Nature; Neurosciences; Norway; Optics; Organism; Pathogenesis; Phenotype; Physiology; Polishes; Process; Proteins; Rat Genome Database; Rat Strains; Rattus; Rattus norvegicus; Renal function; Research; Research Personnel; Resources; Rodent; Sampling; Single Nucleotide Polymorphism; Socialization; Starch; Structure; System; Tissues; Transcript; United States National Institutes of Health; Variant; Work; base; comparative; cost; disorder risk; genome annotation; genome sequencing; genomic tools; genomic variation; hypertensive; mRNA sequencing; mammalian genome; normotensive; rat genome; reference genome; scaffold; single molecule; trait; transcriptome sequencing; transcriptomics; whole genome

Project Summary: The rat is commonly used as an experimental model to investigate a wide diversity of biological processes of medical relevance. These include neuroscience and brain function, behavioral research, and drug dependency and addiction. Similarly, aspects of cardiovascular and renal function are more readily investigated in the rat where the volumes of fluid within these systems are on a much more manageable scale than in smaller rodents. The utility of rat models for investigation has led to the development of inbred rat strains that harbor medically relevant phenotypes. Such models have drawn on pre-existing, natural genetic variation to fix genomic diversity that creates traits such as disease susceptibility. The existence of such models has spurred genetic investigations that have sought to uncover genetic variation responsible for disease susceptibility traits and to utilize such knowledge to reveal mechanistic aspects of disease pathogenesis. However, rat studies can be impeded by the poor quality of existing rat genomic resources. For example, the rat genome reference sequence is very underdeveloped compared to that of human and mouse. Contiguity of the genome assembly is an order of magnitude smaller and gene annotation is much reduced. Further, the reference genome was generated from the Brown Norway inbred rat strain. This strain is biologically remote from many rat strains used in research. The rat is recognized as a highly adaptable species. Evolutionary biologists have recognized that an essential element of adaptation arises from structural variation events in the genome. For example, the adaptation of humans to high starch diets after the introduction of grain-based agriculture is associated with structural variation in the amylase gene. This structural variation results from gene duplication events that are adaptive in permitting increased carbohydrate digestion. These duplication and other large-scale events cannot be observed and understood simply by alignment of short read genome sequence to the reference genome. Long reads are required to capture structural variation events. The objective of our project is to advance rat genomics resources to increase their utility to ongoing studies of this animal model. To do so, we will use PacBio long read sequencing to capture all genomic variation (SNP and structural). We will assemble de novo the genomes of 9 widely used rat strains. We will also introduce additional annotation of the rat genome to increase the numbers of transcripts and proteins associated with the rat reference genome using long read RNA sequencing. The result of our work will be made available via the Rat Genome Database and by Ensembl and will provide essential research information to the many laboratories that employ rat models in their research.

项目摘要： 大鼠通常用作实验模型来研究多种生物过程， 医学相关性其中包括神经科学和脑功能，行为研究，药物依赖 和上瘾。同样，在大鼠中更容易研究心血管和肾功能方面 其中这些系统内的流体体积比较小的啮齿动物更易于管理。 用于研究的大鼠模型的实用性导致了具有医学意义的近交系大鼠的发展 相关表型。这些模型利用预先存在的自然遗传变异来固定基因组多样性 从而产生疾病易感性等特征。这种模式的存在刺激了基因 这些研究试图揭示导致疾病易感性性状的遗传变异， 利用这些知识来揭示疾病发病机理的机制方面。 然而，现有大鼠基因组资源的质量差可能会阻碍大鼠研究。例如，老鼠 与人类和小鼠相比，基因组参考序列非常不发达。毗连 基因组组装小了一个数量级，基因注释也大大减少。此外，参考 从Brown Norway近交系大鼠品系产生基因组。这一品系在生物学上与许多鼠种相距甚远 用于研究的菌株。 老鼠被认为是一种适应性很强的物种。进化生物学家已经认识到， 适应的元素来自基因组中的结构变异事件。例如， 人类高淀粉饮食后引入粮食为基础的农业是与结构变化 在淀粉酶基因中。这种结构变异是由基因复制事件引起的，基因复制事件是适应性的， 增加碳水化合物消化。这些重复和其他大规模事件无法观察到， 通过短读段基因组序列与参考基因组的比对可以简单地理解。长读是 需要捕捉结构变化事件。 我们项目的目标是推进大鼠基因组学资源，以增加其对正在进行的以下研究的效用： 这个动物模型。为此，我们将使用PacBio长读段测序来捕获所有基因组变异（SNP和SNP）。 结构）。我们将重新组装9种广泛使用的大鼠品系的基因组。我们还将推出更多 注释大鼠基因组以增加与大鼠相关的转录物和蛋白质的数量 参考基因组使用长读段RNA测序。我们的工作成果将通过Rat 基因组数据库和Ensembl，并将提供必要的研究信息，许多实验室， 在研究中使用老鼠模型。