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Genomic Sequencing of Japanese Macaques to Enhance NHP Model Discovery

日本猕猴基因组测序以增强 NHP 模型发现

基本信息

批准号：
10834656
负责人：
BETSY M FERGUSON
金额：
$ 44.61万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10834656
关键词：
Acceleration Address Alleles Anatomy Animal Model Animals Behavior Biomedical Research Brain Breeding Cell Therapy Characteristics Childhood Chromosome Mapping Clinical Clinical Data Collaborations Data Data Set Demyelinating Diseases Development Disease model Drusen Ear Encephalomyelitis Ensure Eye FDA approved Funding Future Gene Frequency Generations Genes Genetic Genetic Diseases Genetic Models Genetic Risk Genetic Variation Genome Genomics Genotype Gifts Government Health Hereditary Disease Human Human Genetics Impairment Induced Mutation Institution Japan Japanese Monkey Link Macaca Macaca mulatta Macular degeneration Methods Modeling Multiple Sclerosis Neurodegenerative Disorders Neuronal Ceroid-Lipofuscinosis Nuclear Oregon Pathogenicity Phenotype Physiology Population Population Study Primate Diseases Primates Proteins R24 Radiation Recording of previous events Reporting Research Research Personnel Resources Sensory Single Nucleotide Polymorphism Source Speed Spielmeyer-Vogt Disease Structure Study models United States National Institutes of Health Variant Work analysis pipeline base data modeling early onset gene therapy genetic analysis genetic variant genome sequencing genome-wide genomic data human disease human model member nonhuman primate novel novel therapeutics phenotypic data pre-clinical pre-clinical research precision medicine preclinical study preservation prevent research clinical testing risk variant tool trait user-friendly web site whole genome

项目摘要

SUMMARY The FDA approved the first gene therapy treatment for an inherited disease in late 2017. Since then, an accelerating number of reports describe progress in the development of gene or cell-based therapies to prevent or forestall a range of devastating genetic diseases. The exciting advances in these and other precision medicine approaches have resulted in the rapidly growing demand for genetically similar, large animal models for the pre- clinical study of promising treatments. In that regard, nonhuman primates (NHPs) have emerged as a premier model for the study of human genetic diseases and cutting-edge treatments. In addition to their similar genetics, physiology, anatomy and behavior, the uniquely similar eye, ear and brain structures make macaques particularly important for advancing new therapies to address neurodegenerative disease and sensory impairment. Born out of that need, NIH funded the development of the macaque Genotype and Phenotype (mGAP) Resource, which currently includes genomic sequence and variant data from more than 3.4K rhesus macaques housed in NIH supported colonies. Using state-of-the-art variant discovery methods, mGAP also provides access to discovered single nucleotide variant data, with annotations including predicted protein effects, pathogenicity scores, allele frequency, cross-species conservation metrics and genotype data. The breadth of the primarily US-based mGAP user base underscores the value of this data for clinical and research applications. This current project aims to expand the mGAP data set to include genomic data from a unique Japanese macaque (JM; M. fuscata) colony, founded almost 60 years ago with breeders obtained from the Hiroshima Prefecture and donated to the Oregon National Primate Research Center by the government of Japan. Subsequent generations of breeding among the free-range JM troop has yielded multiple natural models of human disease, including the only known spontaneous model of demyelinating disease similar to multiple sclerosis (MS), a model of Batten Disease (BD), and a dominant drusen model of early-onset macular degeneration (MD). This project will capitalize on the unique history and value of the JM colony by producing whole-genome sequence and variant discovery on the current and future breeders in this colony. The data will enable 1) the discovery and analysis of JM sequence variants, 2) public access to comprehensive genomic data from this unique colony, 3) genetic mapping of the valuable MS and MD models, 4) identification of potential new models based on genome-wide discovery of pathogenic variants, and 5) informed genetic management of the JM colony to insure genetic health and retention of valuable model alleles. All of the generated sequence, variant and associated model data will be made publicly available by the addition of new JM-specific data tracks in the well-established mGAP Resource website.

总结 FDA于2017年底批准了第一种遗传性疾病的基因治疗。从那时起，越来越多的报告描述了基因或细胞为基础的治疗，以防止进展或预防一系列毁灭性的遗传疾病。这些和其他精准医学的令人兴奋的进步这些方法导致了对遗传相似的大型动物模型的快速增长的需求，有希望的治疗方法的临床研究。在这方面，非人灵长类动物（NHP）已经成为一个首要的人类遗传疾病和尖端治疗研究的模型。除了相似的基因，生理学、解剖学和行为学上，独特的相似的眼睛、耳朵和大脑结构使猕猴特别这对于推进新疗法以解决神经退行性疾病和感觉障碍非常重要。非为了满足这一需求，NIH资助了猕猴基因型和表型（mGAP）资源的开发，目前包括来自NIH的3.4K多只恒河猴的基因组序列和变异数据支持殖民地。使用最先进的变体发现方法，mGAP还提供了对已发现的单核苷酸变异数据，注释包括预测的蛋白质效应、致病性评分、等位基因频率，跨物种保护指标和基因型数据。主要基于美国的mGAP的广度用户群强调了这些数据对于临床和研究应用的价值。本项目旨在扩展mGAP数据集以包括来自独特的日本猕猴的基因组数据（JM; M. fuscata）菌落，大约60年前成立，饲养员来自广岛县，捐赠给俄勒冈州日本国家灵长类动物研究中心。后代的繁殖，自由放养的JM部队已经产生了多种人类疾病的自然模型，包括唯一已知的类似于多发性硬化症（MS）的脱髓鞘疾病的自发模型，Batten病（BD）的模型，和早发性黄斑变性（MD）的显性玻璃疣模型。该项目将利用独特的历史和价值的JM殖民地通过生产全基因组序列和变异发现的电流和未来的繁殖者这些数据将使1）发现和分析JM序列变体， 2)公众可以从这个独特的殖民地获得全面的基因组数据，3）有价值的基因图谱 MS和MD模型，4）基于病原体的全基因组发现的潜在新模型的鉴定变种，和5）知情的遗传管理的JM殖民地，以确保遗传健康和保留有价值的模式等位基因所有生成的序列、变体和相关模型数据都将公开提供通过在完善的mGAP资源网站中增加新的JM特定数据轨道。