Host genetic variation affecting the microbiome in rhesus macaques

项目摘要 越来越多的文献关注微生物组与人类疾病的关联， 肥胖症、II型糖尿病、心血管疾病、癌症和精神疾病如自闭症， 精神分裂症和抑郁症虽然这些协会仍然相对较新，而且在很大程度上是相互关联的， 并没有阻止旨在操纵微生物组的治疗方法的发展， 努力治疗这些疾病。然而，围绕微生物组仍存在大量未知数 范围从负责其组成的因素到个体间变异的性质和来源 微生物组和疾病之间的实际因果关系，特别是在人类中。这是复杂的， 人类和啮齿类动物模型之间的生理学和微生物组组成的差异，以及 环境对人类的影响无法控制。这个提议用了1300只恒河猴 从4个菌落中分离，以研究胃肠道、口腔和鼻腔微生物组的变异性。它将描述 动物间存在的个体间差异，并进一步将恒河猴作为模型 用于人类微生物组研究。利用800只动物的全基因组序列和500 动物与整个外显子组序列可用，我们还提出了全基因组和外显子组的关联 研究微生物组多样性和特定细菌分类群的措施。这些数据可以用于 补充和关注微生物组的人类遗传研究。这不仅会加深我们对 影响微生物组组成的因素，但它也将有助于灵长类动物模型的发展， 测试疾病与微生物组的关联，并测试治疗干预改变微生物组的能力。 微生物组

PROJECT SUMMARY An increasing body of literature has focused on associating the microbiome with human diseases including obesity, type II diabetes, cardiovascular disease, cancers, and psychiatric disorders such as autism, schizophrenia, and depression. While these associations are still relatively nascent and largely correlative, it has not stopped the push towards development of therapeutics aimed at manipulating the microbiome in an effort to treat these disorders. There remain, however, a great deal of unknowns surrounding the microbiome ranging from the factors responsible for its composition to the nature and sources of inter-individual variability to the actual causative links between microbiome and disease, particularly in humans. This is complicated by differences in physiology and microbiome composition between humans and rodent models and the pervasive effects of the environment that cannot be controlled for in humans. This proposal uses 1300 rhesus macaques from 4 colonies to investigate variability in the gastrointestinal, oral, and nasal microbiome. It will characterize the inter-individual variability that exists across animals and further develop the rhesus macaque as a model for human microbiome studies. Leveraging 800 animals with whole genome sequence available and 500 animals with whole exome sequence available, we also propose genome-wide and exome-wide association studies on measures of microbiome diversity and specific bacterial taxa. This data can then be used to complement and focus human genetic studies of the microbiome. This will not only further our understanding of factors that affect microbiome composition, but it will also assist in the development of primate models for testing disease associations with the microbiome and for testing the ability of therapeutic interventions to alter the microbiome.