Genomic sequencing to establish a macaque genotype and phenotype research resource

项目摘要 这个R24应用程序解决了NIH的优先事项，以扩大非人灵长类动物（NHP）菌落的遗传分析， 以使所得到的基因组变异数据可重复访问，并促进NHP模型的发现。这些 这些目标反映了迫切需要确定遗传学上合适的大型动物模型，以支持 开发精确的医学方法，包括基于基因或细胞的疗法，用于治疗 人类疾病在这方面，NHP，特别是恒河猴，已经成为临床前的首选动物。 模型，由于其相似的遗传内容，生理和解剖，特别是独特的相似的眼睛，耳朵， 以及对治疗神经变性疾病和感觉障碍很重要的脑结构。我们 已经表明恒河猴携带数千种变异， 与遗传疾病相关的等位基因，或被预测为功能性损害并可能导致 疾病这种R24研究资源将通过测序有效地识别这种预测的致病性变体， 多产繁殖者的基因组，这些繁殖者总共生产了4,200多只猕猴， 三个大的，NIH支持恒河猴繁殖殖民地。通过将多个育种中心纳入其中， 研究，有更多的机会来确定罕见的序列变异，如果需要，建立育种 传播重大疾病模型的计划。通过与兽医专家、调查人员和 临床医生描述最迫切需要的疾病模型，我们将继续确定新的自然 发生的NHP遗传模型，可用于研究和治疗人类疾病相关 听力障碍、失明、神经退化或发育障碍等。所有 该项目产生的基因组序列、变体和模型数据将通过我们的网站提供， 可访问的，猕猴基因型和表型（mGAP）研究资源，唯一的公共资源，提供 NIH国家灵长类动物研究中心饲养的恒河猴的个体连锁基因型数据 （NPRCs）。mGAP已经吸引了广泛的研究人员和临床医生的使用。除了 部署新的mGAP功能，变体和猕猴注释，我们还将分析和宿主恒河猴 其他NIH资助的研究产生的猕猴基因组数据集。因此，mGAP将继续服务于 作为共享全国NPRC饲养的恒河猴基因组变异数据的中心资源， 支持NIH恒河猴群体的先进遗传管理，并扩大 预防或减轻人类疾病的新医疗方法的发展。

PROJECT SUMMARY This R24 application addresses NIH priorities to expand genetic analysis of nonhuman primate (NHP) colonies, to make the resulting genomic variant data publically accessible, and to promote NHP model discovery. These goals reflect the urgent need for the identification of genetically appropriate, large-animal models to support the development of precision medicine approaches, including gene or cell-based therapies, for the treatment of human disease. In that regard, NHPs, especially rhesus macaques, have emerged as a premier pre-clinical model, owing to their similar genetic content, physiology and anatomy, particularly the uniquely similar eye, ear and brain structures important for the treatment of neurodegenerative disease and sensory impairment. We have shown that rhesus macaques carry thousands of variants that are either identical to human pathogenic alleles associated with genetic disease, or are predicted to be functionally damaging and likely contributing to disease. This R24 research resource will efficiently identify such predicted pathogenic variants, by sequencing the genomes of prolific breeders that together produced more than 4,200 of the macaques currently living in three large, NIH supported rhesus macaque breeding colonies. By including multiple breeding centers in this study, there are increased opportunities to identify rare sequence variants, and if needed, to establish breeding programs to propagate critical disease models. By working with veterinary specialists, investigators and clinicians to characterize the most urgently needed disease models, we will continue to identify new naturally occurring NHP genetic models that can be utilized for the study and treatment of human diseases associated with hearing impairment, blindness, neurodegeneration or developmental disorders, among others. All of the genome sequences, variants and model data generated by this project will be made available through our web- accessible, macaque Genotype And Phenotype (mGAP) research resource, the only public resource to provide individual-linked genotype data for rhesus macaques housed at the NIH National Primate Research Centers (NPRCs). mGAP has already attracted use by a broad range of investigators and clinicians. In addition to deploying new mGAP functions, variants and macaque annotations, we will also analyze and host rhesus macaque genomic data sets produced by other NIH-funded studies. Accordingly, mGAP will continue to serve as a central resource for sharing genomic variant data on rhesus macaques housed at NPRCs nationwide, supporting advanced genetic management of NIH rhesus macaque colonies, and expanding opportunities for the development of new medical treatments to prevent or alleviate human disease.