Fine-scale recombination rate variation within and between Drosophila species

描述（由申请人提供）：本主题专门针对发展对遗传图谱和物种内和物种间重组的深入和多样的理解，这是我们的提案打算研究的内容。项目名称：果蝇种内和种间的精细重组率差异。 在过去的二十年里，NIH、NSF、USDA和DOE已经在基因组测序上投入了数十亿美元。这些基因组计划使我们对疾病的生物学基础有了新的认识，导致了新的诊断工具的产生，最近还促进了高通量重测序技术（HTseq）的发展，这些技术正在彻底改变生物医学研究。有了这些最新的技术突破，研究人员可以重新测序任何个人的全基因组，成本接近“千美元基因组”。由此产生的数据将通过增强我们对个体独特性的理解，帮助医生为个体量身定制治疗，确定许多疾病的易感性，病因学和发病机制的新遗传决定因素，并通常使我们对生物学有更深入的了解，从而迎来“个性化医疗”的时代。理解这些新发现的基因组数据财富是新的挑战。关键的未解决的问题是，生物学相关的变异存在于何处，以及形成这种变异的结构、进化和遗传过程是什么？减数分裂重组是这两个问题的核心。遗传作图仍然是我们发现遗传和表型变异之间有意义关联的主要工具之一。在大多数真核生物中，重组对于确保正确的染色体分离、促进DNA修复和为遗传多样性提供基础至关重要。通过打破基因座之间的连锁关系，突变也允许不同的基因组区域具有不同的进化历史。这个为期2年的多PI项目的结果将填补我们对生物学基本参数之一的基础知识的空白：重组。该项目产生的遗传图谱的收集将提供前所未有的洞察力，如何重组内和种群之间和物种之间的变化。我们的数据将成为对群体遗传学和全基因组关联研究感兴趣的大型和异质性科学界的关键资源。 公共卫生相关性：虽然全基因组关联研究（WGA）已经成功地确定了许多与疾病和复杂性状（如糖尿病）相关的新基因座，但这些基因座只能解释这些性状遗传力的一小部分。然而，WGA的研究假设重组率在物种内的个体之间是不变的，这一假设要么是不合理的，要么是不真实的。我们对果蝇种群内重组率如何变化的综合研究结果-一种常用的关联研究模型系统-将重塑人类WGA的执行方式，并为新一代WGA模型和工具奠定基础。

DESCRIPTION (provided by applicant): This topic specifically targets developing a deep and diverse understanding of genetic maps and recombination within and between species, which is what our proposal intends to study. Project Title: Fine-scale recombination rate variation within and between Drosophila species. Over the past two decades the NIH, NSF, USDA, and DOE have invested billions of dollars into genomic sequencing. These genome projects have given us new insight into the biological basis of disease, led to the production of new diagnostic tools, and recently contributed to the development of high throughput resequencing technologies (HTseq) that are revolutionizing biomedical research. With these recent technological breakthroughs, researchers can resequence the full genome of any individual at costs approaching a "thousand dollar genome." The resultant data will usher in an era of "personalized medicine" by enhancing our understanding of what makes individuals unique, helping physicians tailor treatments to individuals, identifying new genetic determinants for the susceptibility, etiology, and pathogenesis of many diseases, and generally giving us a deeper understanding of biology. Making sense of this new found wealth of genomic data is the new challenge. Key unsolved questions are where does the biologically relevant variation reside and what are the structural, evolutionary, and genetic processes shaping this variation? Meiotic recombination lies at the nexus of these two questions. Genetic mapping remains one of our primary tools for uncovering meaningful associations between genetic and phenotypic variation. In most eukaryotes, recombination is critical for ensuring proper chromosome segregation, facilitating DNA repair, and providing a basis for genetic diversity. Recombination, by breaking up linkage relationships among loci, also allows different genomic regions to have different evolutionary histories. The results of this multi-PI, 2-year project will fill in a gap in our basic knowledge of one of the fundamental parameters in biology: recombination. The collection of genetic maps produced by this project will provide an unprecedented insight how recombination varies within and between populations and among species. Our data will be a critical resource for the large and heterogeneous scientific community interested in population genetics and whole genome association studies. PUBLIC HEALTH RELEVANCE: While whole genome association studies (WGA) have be successful in identifying a number of new loci associated with diseases and complex traits, such as diabetes, these loci only explain a fraction of the heritability of these traits. WGA studies, however, assume that recombination rates are invariant among individuals within species, an assumption that is either unjustified or untrue. The results of our comprehensive study on how recombination rates vary within populations of Drosophila - a commonly used model system for association studies - will reshape how human WGA are performed and lay out the foundation for a new generation of WGA models and tools.