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: 10615135
• 负责人: PETER A DORIS
• 金额: $ 39.85万
• 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/10615135
• 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; Maps; 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; X Inactivation; base; comparative; cost; disorder risk; genome annotation; genome resource; 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： 大鼠通常用作一个实验模型，以研究广泛的生物学过程的多样性 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 这些系统中流体的体积比较小的啮齿动物更易于管理。 大鼠模型进行调查的实用性导致了近交大鼠菌株的发展 相关表型。此类模型已借鉴了既有自然遗传变异来固定基因组多样性 这会产生诸如疾病易感性之类的特征。这种模型的存在刺激了遗传 试图发现负责疾病易感特征的遗传变异的调查和 利用这种知识来揭示疾病发病机理的机理方面。 但是，现有大鼠基因组资源质量差会阻碍大鼠研究。例如，老鼠 与人和小鼠相比，基因组参考序列非常不发达。续签 基因组组装是一个较小的数量级，基因注释大大降低。此外，参考 基因组是由棕色挪威近交大鼠菌株产生的。这种菌株在生物学上远离许多老鼠 研究中使用的菌株。 大鼠被认为是高度适应性的物种。进化生物学家已经认识到这是必不可少的 适应性元素来自基因组中的结构变异事件。例如，改编 引入基于谷物的农业后，人类至高淀粉饮食与结构变化有关 在淀粉酶基因中。这种结构变化是由自适应允许的基因复制事件引起的 碳水化合物消化增加。这些重复和其他大规模事件无法观察到 仅通过对参考基因组的简短读取基因组序列的比对来理解。长阅读是 捕获结构变化事件所需。 我们项目的目的是促进大鼠基因组学资源，以提高其实用性 这个动物模型。为此，我们将使用PACBIO长阅读测序来捕获所有基因组变异（SNP和 结构）。我们将从从头组装9种广泛使用的大鼠菌株的基因组。我们还将介绍其他 大鼠基因组的注释以增加与大鼠相关的转录本和蛋白质的数量 使用长读RNA测序参考基因组。我们工作的结果将通过老鼠提供 基因组数据库并通过Ensembl，并将向许多实验室提供基本的研究信息 在他们的研究中采用大鼠模型。

项目成果

Polygenic genetic variation affecting antibody formation underlies hypertensive renal injury in the stroke-prone spontaneously hypertensive rat.

影响抗体形成的多基因遗传变异是易发生中风的自发性高血压大鼠高血压肾损伤的基础。

• DOI: 10.1152/ajprenal.00058.2023
• 发表时间: 2023
• 期刊: American journal of physiology. Renal physiology
• 作者: Dhande,IshaS;Zhu,Yaming;Joshi,AniketS;Hicks,MJohn;Braun,MichaelC;Doris,PeterA
• 通讯作者: Doris,PeterA

The Assembled Genome of the Stroke-Prone Spontaneously Hypertensive Rat.

易中风的自发性高血压大鼠的组装基因组。

• DOI: 10.1161/hypertensionaha.122.20140
• 发表时间: 2023
• 期刊: Hypertension (Dallas, Tex. : 1979)
• 作者: Kalbfleisch,TheodoreS;HussienAbouElEla,NahlaA;Li,Kai;Brashear,WesleyA;Kochan,KelliJ;Hillhouse,AndrewE;Zhu,Yaming;Dhande,IshaS;Kline,EricJ;Hudson,ElizabethA;Murphy,TerenceD;Thibaud-Nissen,Françoise;Smith,MelissaL;Doris
• 通讯作者: Doris

mRatBN7.2: familiar and unfamiliar features of a new rat genome reference assembly.

mRatBN7.2：新的大鼠基因组参考组件的熟悉和不熟悉的特征。

• DOI: 10.1152/physiolgenomics.00017.2022
• 发表时间: 2022
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: deJong,TristanV;Chen,Hao;Brashear,WesleyA;Kochan,KelliJ;Hillhouse,AndrewE;Zhu,Yaming;Dhande,IshaS;Hudson,ElizabethA;Sumlut,MaryH;Smith,MelissaL;Kalbfleisch,TheodoreS;Doris,PeterA
• 通讯作者: Doris,PeterA