Genomic sequencing to establish a macaque genotype and phenotype research resource

项目总结 这个R24应用程序解决了NIH的优先事项，以扩大对非人灵长类(NHP)群体的遗传分析， 使由此产生的基因组变异数据公开，并促进NHP模型的发现。这些 目标反映了迫切需要确定遗传上合适的大型动物模型，以支持 发展精准医学方法，包括基于基因或细胞的治疗方法，用于治疗 人类疾病。在这方面，NHP，特别是恒河猴，已经成为首要的临床前研究对象。 模型，由于他们相似的遗传内容，生理和解剖，特别是唯一相似的眼睛，耳朵 以及对治疗神经退行性疾病和感觉障碍很重要的大脑结构。我们 已经证明恒河猴携带数千种变种，这些变种要么与人类致病基因相同 与遗传病相关的等位基因，或被预测为功能损害并可能导致 疾病。这个R24研究资源将通过测序有效地识别这些预测的致病变异 多产繁殖者的基因组，这些繁殖者总共产生了4200多只目前生活在 美国国立卫生研究院支持三个大型恒河猴繁殖群体。通过将多个育种中心包括在此 研究表明，识别稀有序列变异的机会增加了，如果需要，还可以建立育种 传播危重疾病模型的计划。通过与兽医专家、调查人员和 临床医生对最迫切需要的疾病模型进行定性，我们将继续自然地识别新的 可用于研究和治疗人类相关疾病的正在发生的NHP遗传模型 有听力障碍、失明、神经变性或发育障碍等。所有的 该项目产生的基因组序列、变异体和模型数据将通过我们的网络- 可访问的猕猴基因类型和表型(MGAP)研究资源，是唯一提供 美国国立卫生研究院国家灵长类研究中心猕猴的个体连锁基因数据 (全国人民代表大会)。MGAP已经吸引了广泛的研究人员和临床医生的使用。除了……之外 部署新的mGAP函数、变体和猕猴注释，我们还将分析和托管恒河猴 由美国国立卫生研究院资助的其他研究产生的猕猴基因组数据集。因此，mGAP将继续提供服务 作为共享全国猕猴基因组变异数据的中心资源， 支持NIH恒河猴群体的高级遗传管理，并扩大 开发新的医疗方法来预防或减轻人类疾病。

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.