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Exome screening and directed breeding of rhesus for human genetic disease models

人类遗传病模型的恒河猴外显子筛选和定向育种

基本信息

批准号：
9111085
负责人：
R. PAUL JOHNSON
金额：
$ 24.79万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9111085
关键词：
ABCB1 gene Affect Animal Model Animals Breeding CYP21A2 gene Cataloging Catalogs Data Development Dideoxy Chain Termination DNA Sequencing Disease Disease model Embryo Exhibits Female Funding Gene Mutation Genes Genetic Genetic Polymorphism Genetic Screening Genome Genotype Goals Health Hereditary Disease Heterozygote Human Human Genetics Institutes Institution Macaca mulatta Maryland Mendelian disorder Methods Modeling Monkeys Mus Mutation Orthologous Gene Phenotype Physiology Population Pre-Clinical Model Primates Proteins Research System Universities Validation animal breeding base cost disease phenotype drug development exome exome sequencing expectation human disease loss of function loss of function mutation male mutant nonhuman primate offspring pre-clinical research screening therapy development translational study treatment strategy

项目摘要

DESCRIPTION (provided by applicant): There are over 6000 disorders in humans that result from a single gene mutation (Rappaport et al. 2013). For many of these conditions, there is no suitable animal model. Because rhesus macaques are genetically and physiologically similar to humans, they have the potential to offer preclinical models for numerous human conditions. We have preliminary data demonstrating that we can identify loss-of-function mutations in rhesus macaques related to human disease from exome sequencing, validate these results with PCR and Sanger sequencing and establish loss-of-function at the protein level. The overall goal of this proposal is to produce rhesus macaque models of single gene human genetic disorders. To accomplish this, we will identify naturally occurring loss-of-function mutations in rhesus macaques at the Yerkes National Primate Research Center (YNPRC). We already have exome sequence data from 61 animals. We will identify loss- of-function mutations in genes using the GATK pipeline and then validate these mutations with PCR/Sanger sequencing. Because these mutations are likely to be present in the heterozygous state, we propose to genotype 500 breeding rhesus macaques for a subset of the newly identified loci. The loci we choose to genotype will be based on whether the polymorphism leads to a predicted loss of function within genes implicated in human disease. After genotyping and identification of a sufficient number of animals that have the same mutation, we will breed multiple male and female heterozygotes with the expectation that 25% of the resulting offspring will be homozygous for the mutation. We expect that these animals will exhibit a phenotype similar to humans with loss-of-function mutations in the orthologous gene and serve as models for preclinical translational studies to begin to identify possible treatment strategies. When completed, this proposal will produce three distinct deliverables. 1) A catalog of high impact polymorphism present within a subset of the Yerkes rhesus population. 2) "Proof of concept" in an affected offspring that will serve as a model in the study of human single gene disorders. 3) Development of a pipeline to produce additional rhesus models of human genetic disease at Yerkes and other institutions.

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Naturally Occurring Genetic Variants of Human Acetylcholinesterase and Butyrylcholinesterase and Their Potential Impact on the Risk of Toxicity from Cholinesterase Inhibitors.

DOI：
10.1021/acs.chemrestox.6b00228
发表时间：
2016-09-19
期刊：
CHEMICAL RESEARCH IN TOXICOLOGY
影响因子：
4.1
作者：
Lockridge, Oksana;Norgren, Robert B., Jr.;Johnson, Rudolph C.;Blake, Thomas A.
通讯作者：
Blake, Thomas A.