Genetic dissection of trait variation between long-diverged mouse species

长期分化小鼠物种之间性状变异的遗传剖析

基本信息

批准号：
9790596
负责人：
Diana Michele Bautista
金额：
$ 69.6万
依托单位：
BUCK INSTITUTE FOR RESEARCH ON AGING
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9790596
关键词：
Age Alleles Amaze Amphibia Animals Attention Axon Beauty Biological Assay Biology Butterflies Catalogs Cessation of life DNA Sequence Diploidy Disease Disease Resistance Dissection Dreams Drug Design Environment Evolution Experimental Genetics Genes Genetic Genetic Variation Genotype Goals High-Throughput Nucleotide Sequencing Human Hybrids Individual Injury Laboratory mice Life Limb structure Literature Logic Longevity Love Malignant Neoplasms Mammalian Cell Mammals Maps Methods Modernization Mole Rats Molecular Mosaicism Mus Mutagenesis Mutation Natural Resistance Natural Selections Natural regeneration Nature Neuraxis Neurons Organism Panthera leo Parents Partner in relationship Patients Phenotype Pilot Projects Planets Plant Roots Plants Population Problem Solving Process Recombinants Resistance Saccharomyces Sister Site Sterility Stress Stroke Testing Textbooks Time Traction Trauma Trauma patient Traumatic Brain Injury Trees Variant Viral Virus Wing Work Yeasts axon regeneration design embryonic stem cell experimental study feeding fictional works genome wide association study genome-wide innovation interest member mimetics mutant novel strategies offspring post stroke pressure programs reproductive species difference tool trait

项目摘要

PROJECT SUMMARY/ABSTRACT Over the four billion years that life has evolved on this planet, organisms have acquired amazing phenotypes. Some, like lions' manes and butterflies' wings, capture our attention by their sheer beauty. Others get us excited in a very different way—their relevance to biomedicine. Ecologists have catalogued remarkable disease and stress resistance traits in the plant and animal worlds, which have arisen to solve problems similar to those in human patients. We'd love to know the molecular basis of these natural resistance phenotypes, so that we can design drugs to mimic them in the biomedical context. However, most often, we know about a given trait because it is a defining feature of its respective species, acquired long ago to adapt to a unique niche. Now, millions of years later, the species usually has lost the ability to interbreed with relatives in other environments. And this reproductive isolation is a death knell for existing tools to map genotype to phenotype. The latter, which fill the pages of the modern genetics literature, rely on big panels of recombinant progeny from matings between distinct parents. These tools are no use in the study of species that can't mate to form progeny in the first place. We have developed a new strategy to break through this roadblock, and map the genetic basis of trait variation between long-diverged species. Our approach starts with a viable, but sterile, interspecific hybrid. In this hybrid, at a given gene, we introduce mutations to disrupt each of the two alleles in turn from the two species parents. These hemizygote mutants are identical with respect to background, except that at the target gene, each strain expresses a wild-type allele from only one of the parents. As such, if the hemizygotes differ with respect to a trait of interest, we infer that it must be because of functional allelic variation at the manipulated site. We have pioneered a genome-scale pipeline for this so-called reciprocal hemizygosity test, which we call RH-seq, using yeast as proof of concept. In the current proposal we describe experiments to port RH-seq to mammalian cells. We focus on a little-studied mouse species, M. castaneus, which can regrow axons of the central nervous system after injury. The genes we find in this pioneering study will serve as a springboard for drug design for stroke and brain trauma patients. And our metazoan RH-seq approach will pave the way for the genetic dissection of trait variation between species across Eukarya.

项目摘要/摘要在这个星球上生命发展的四十亿年中，生物已经获得了惊人的表型。有些，例如狮子的鬃毛和蝴蝶的翅膀，它们的纯粹美丽吸引了我们的注意。其他人得到我们以非常不同的方式激发与生物医学的相关性。生态学家已经归类了动植物世界中的疾病和压力抗性特征，这些特征已经出现了以解决类似问题的问题对于人类患者的人。我们很想知道这些自然抗性表型的分子基础，因此我们可以在生物医学背景下设计药物来模仿它们。但是，大多数情况下，我们知道给定特征是因为它是其相对物种的定义特征，很久以前就可以适应独特利基。现在，数百万年后，该物种通常失去与其他亲戚杂交的能力环境。这种生殖隔离是现有工具将基因型映射到表型的死亡跪。后来填补了现代遗传学文献的页面，依靠重组进度的大型面板从不同父母之间的陈述。这些工具在无法形成的物种的研究中没有用后代首先。我们已经制定了一种破坏这一障碍的新策略，并绘制了特质变化的遗传基础在长期发散的物种之间。我们的方法始于可行但无菌的种间杂交。在这个混合动力，在给定的基因上，我们引入突变，以破坏两个等位基因的每个等位基因。父母。这些半合子突变体相对于背景是相同的，除了在靶基因处，每种菌株都表达只有一个父母的野生型等位基因。因此，如果半合子与尊重感兴趣的特征，我们推断必须是由于操纵的功能等位基因变化地点。我们已经为这种所谓的倒数半合子测试率先开创了基因组规模的管道，我们称之为 Rh-Seq，使用酵母作为概念证明。在当前的建议中，我们描述了港口Rh-Seq的实验哺乳动物细胞。我们专注于一个有点研究的小鼠种类，Castaneus，可以完善的轴突受伤后中枢神经系统。我们在这项开创性研究中发现的基因将作为跳板中风和脑创伤患者的药物设计。我们的后生Rh-Seq方法将为真实性物种之间性状变化的遗传解剖。