Genetic studies of a pleiotropic transmembrane protease: insight from color variation in non-model organisms

多效性跨膜蛋白酶的遗传研究：从非模型生物体颜色变化中获得洞察

基本信息

批准号：
10754001
负责人：
Gregory Stefan Barsh
金额：
$ 30.68万
依托单位：
HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-04 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10754001
关键词：
Admixture Affect Aminopeptidase Animals Area Asian Biological Process Black Panther Breeding Candidate Disease Gene Cell Culture Techniques Characteristics Cheetahs Color Communities DNA Darkness Development Domestic Animals Enteric Nervous System Exhibits Experimental Genetics Family Felidae Felis catus Genes Genetic Genetic study Hair Hair Color Heritability Human Human Biology Individual Investigation Knockout Mice Laboratory Study Laboratory mice Mammalian Cell Mammals Marble Melanogenesis Membrane Molecular Morphology Mus Mutant Strains Mice Mutation Names Organism Palate Pathway interactions Pattern Peptide Hydrolases Phenotype Pigmentation physiologic function Placental Biology Placentation Population Proteomics Research Role Rwanda Sampling Signal Pathway Signal Transduction Skin Spottings System Technology Testing Tigers Tissue Sample Tissues Variant WNT Signaling Pathway Wild Animals Work Zebra causal variant cell type experimental study fetal forward genetics gene discovery gene interaction genetic approach genetic association genetic pedigree genetic resource genetic variant genome sequencing genome wide association study human disease inhibitor insight loss of function model organism mouse genetics novel self organization trait transcriptomics whole genome

项目摘要

Project Summary/Abstract Mendelian variation in pigmentation is a rich genetic resource to identify and study signaling pathways relevant to human biology, but the repertoire of mutations that affect pigmentation in mice and in humans coat color has become saturated. Advances in genome sequencing technology now extend the reach of forward genetics beyond humans and model organisms to domestic and wild animals, for which there are many pigmentary phenotypes likely to represent conserved signaling pathways but whose molecular basis is unknown. Using pigmentary variation in domestic cats, our research group discovered a striking connection between a novel transmembrane protease encoded by Transmembrane aminopeptidase Q (Taqpep) and a secreted Wnt inhibitor encoded by Dickkopf 4 (Dkk4). Initial studies of Taqpep knockout mice reveal a role in multiple cell types and tissues including hair, the enteric nervous system, and the palate. In a different non-model organism, the plains zebra, Taqpep is a candidate gene for aberrant striping in an isolated population in Rwanda. Our results point to a central role for Taqpep in pathways and tissues that are directly relevant to human biology and disease, but a molecular understanding of those pathways is most effectively approached by combining forward genetics for gene discovery in non-model mammalian organisms with experimental genetics in laboratory mice and studies in cultured mammalian cells. We propose to: (1) Identify additional components of Taqpep action by forward genetics in Bengal cats and by analysis of fetal cat skin (2) Expand initial genetic studies of color pattern variation in zebras (3) Determine the mechanism of Taqpep action using experimental mouse genetics and proteomics

项目摘要/摘要 Mendelian色素沉着的变异是识别和研究信号通路相关的丰富遗传资源人类生物学，但影响小鼠和人类外套色素沉着的突变的曲目具有变得饱和。基因组测序技术的进步现在扩展了远期遗传学的范围除了人类和模型的生物外，还有许多色素表型可能代表了保守的信号通路，但其分子基础尚不清楚。我们的研究小组使用了家猫的色素变异，发现由跨膜氨基肽酶Q（Taqpep）和分泌的Wnt编码的新型跨膜蛋白酶由Dickkopf 4（DKK4）编码的抑制剂。 Taqpep敲除小鼠的初步研究揭示了在多个细胞中的作用包括头发，肠神经系统和口感在内的类型和组织。在不同的非模型生物中，平原斑马，Taqpep是卢旺达孤立人群中异常条纹的候选基因。我们的结果表明，taqpep在与人类直接相关的途径和组织中的核心作用生物学和疾病，但是对这些途径的分子理解最有效地接近了将非模型哺乳动物生物中基因发现的正向遗传学与实验遗传学相结合在实验室小鼠和培养的哺乳动物细胞中的研究中。我们建议：（1）通过孟加拉猫的正向遗传学确定TAQPEP作用的其他组成部分和胎儿分析猫皮（2）扩大斑马颜色模式变化的初始遗传研究（3）使用实验小鼠遗传学和蛋白质组学确定TAQPEP作用的机制