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

基本信息

批准号：
10211748
负责人：
PETER A DORIS
金额：
$ 45.84万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
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/10211748
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 mRNA sequencing mammalian genome normotensive rat genome reference genome scaffold single molecule trait transcriptome sequencing transcriptomics whole genome

项目摘要

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.

项目概要：大鼠通常用作实验模型来研究多种生物过程医学相关性。这些包括神经科学和大脑功能、行为研究和药物依赖性和成瘾。同样，在大鼠中更容易研究心血管和肾功能的各个方面这些系统内的液体体积比小型啮齿动物更容易管理。大鼠模型在研究中的应用导致了近交系大鼠品系的发展，这些品系具有医学意义相关表型。这些模型利用了预先存在的自然遗传变异来修复基因组多样性这会产生疾病易感性等特征。这种模型的存在刺激了遗传旨在揭示导致疾病易感性特征的遗传变异并利用这些知识来揭示疾病发病机制的机制。然而，现有大鼠基因组资源质量差可能会阻碍大鼠研究。例如，老鼠与人类和小鼠的基因组参考序列相比，基因组参考序列非常不发达。的连续性基因组组装小了一个数量级，基因注释也大大减少。此外，参考基因组是从棕色挪威近交系大鼠品系产生的。该菌株在生物学上远离许多大鼠研究中使用的菌株。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，一个重要的适应因素源于基因组中的结构变异事件。例如，适应引入以谷物为基础的农业后，人类转向高淀粉饮食与结构变异有关在淀粉酶基因中。这种结构变异是由基因复制事件引起的，这些事件适应性地允许增加碳水化合物的消化。这些重复和其他大规模事件无法被观察到并且简单地通过短读基因组序列与参考基因组的比对来理解。长读是捕获结构变化事件所需的。我们项目的目标是推进大鼠基因组学资源，以提高其对正在进行的研究的效用这个动物模型。为此，我们将使用 PacBio 长读测序来捕获所有基因组变异（SNP 和结构）。我们将从头组装 9 种广泛使用的大鼠品系的基因组。我们还将推出额外的对大鼠基因组进行注释，以增加与大鼠相关的转录物和蛋白质的数量使用长读长RNA测序的参考基因组。我们的工作结果将通过 Rat 公布基因组数据库和 Ensembl 将为许多实验室提供重要的研究信息在他们的研究中使用大鼠模型。