Genetic variation, admixture and genome structure evolution through the lense of Drosophila genomics

从果蝇基因组学的角度观察遗传变异、混合和基因组结构进化

• 批准号: 10447034
• 负责人: Russell Corbett-Detig
• 金额: $ 37.66万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447034
• 关键词: Admixture; Alleles; Animal Model; Automobile Driving; Awareness; Chromatin Conformation Capture and Sequencing; Chromosome inversion; Complex; DNA Sequence Rearrangement; Data; Data Set; Databases; Distributed Databases; Drosophila genome; Drosophila genus; Event; Evolution; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Models; Genetic Variation; Genome; Genome engineering; Genomics; Goals; Haploidy; Hi-C; Inbreeding; Libraries; Link; Location; Maps; Methods; Mutation; Natural Selections; Phenotype; Population; Process; Production; Research; Sampling; Shapes; Single Nucleotide Polymorphism; Structure; System; Techniques; Variant; fitness; gene interaction; genome sequencing; genomic variation; improved; innovation; insight; molecular phenotype; novel; phenotypic data; programs; reference genome; tool; trait

Studies in genetic model organisms are an indispensible mechanism for characterizing the mutational and selective processes that generate genetic and phenotypic diversity. In particular, Drosophila combines the advantages of efficient population sampling, well developed experimental techniques, with powerful genome engineering approaches and is therefore a uniquely valuable system for characterizing the contributions of genetic variation to phenotypic and fitness variation in natural populations. Towards this broad goal, this research program will leverage the D. melanogaster system to: (1) Enhance the Drosophila Genome Nexus (DGN), a widely used database that distributes a uniformly curated and high quality Drosophila population genomic variation dataset. Specifically, by developing methods that include known genetic variation rather than mapping to a single haploid reference genome, this research program will enhance both variation calls at single nucleotide polymorphisms as well as expand our ability to detect and accurately characterize structural variation. Similarly, research will develop and apply approaches for accurately delineating heterozygous regions in the genomes of inbred lines. By vastly improving the database, this reseach will enable a new wave of in-depth analyses of the widely-used DGN. (2) Reveal the fitness and gene expression consequences of the structural and linked allelic variation associated with natural chromosomal inversions. Genome engineering techniques enable the construction of inversions with controlled breakpoints on a genetically homogenous background. Through contrasts with naturally occurring chromosomal inversions, research will distinguish the impacts of structural and linked allelic variation on gene expression patterns. In addition, research will investigate the fitness consequences of fine- scale variation in breakpoint location. Chromatin conformation capture sequencing, Hi-C, will enable the production of sequencing libraries whose large insert sizes enable inversion breakpoint mapping. Research will apply this approach to map breakpoints of rare inversions. By comparing breakpoint structures with those of common inversions, these data will enable direct insights into the mutational forces that generate inversions as well as how these factors influence natural selection on new chromosomal arrangements. (3) Investigate the genomic and phenotypic consequences of admixture between genetically divergent subpopulations. By sequencing several admixed populations of D. melanogaster, research will determine the relative importance of gene-gene interactions in driving natural selection across diverse admixed populations. Furthermore, by leverage phenotypic data from one admixed population that has been used for a number of association studies, research will evaluate the importance of admixture in shaping complex phenotypes long after the initial gene flow event and develop local ancestry aware approaches for mapping complex trait associations.

遗传模型生物的研究是表征突变和突变的不可或缺的机制。 产生遗传和表型多样性的选择性过程。特别是，果蝇结合了 高效的群体采样、发达的实验技术、强大的基因组优势 工程方法，因此是一个独特的有价值的系统，用于表征 自然群体中表型和适应度变异的遗传变异。为实现这一宏伟目标， 研究计划将利用黑腹果蝇系统来： (1) 增强果蝇基因组 Nexus (DGN)，这是一个广泛使用的数据库，可均匀分布 精心策划的高质量果蝇群体基因组变异数据集。具体来说，通过开发 方法包括已知的遗传变异而不是映射到单个单倍体参考基因组，这 研究计划将增强单核苷酸多态性的变异调用，并扩大我们的研究范围 检测和准确表征结构变化的能力。同样，研究将开发和应用 准确描绘自交系基因组中杂合区域的方法。大大地 通过改进数据库，这项研究将为广泛使用的 DGN 带来新一轮的深入分析。 (2) 揭示结构和连锁等位基因变异的适应性和基因表达后果 与自然染色体倒位有关。基因组工程技术使构建成为可能 在遗传同质背景上具有受控断点的反转。通过对比 自然发生的染色体倒位，研究将区分结构和连锁等位基因的影响 基因表达模式的变异。此外，研究还将调查精细训练对健康的影响 断点位置的比例变化。染色质构象捕获测序 Hi-C 将使 生产具有大插入片段的测序文库，可实现反转断点映射。研究将 应用这种方法来映射罕见反转的断点。通过比较断点结构与 常见的反转，这些数据将能够直接洞察产生反转的突变力 以及这些因素如何影响新染色体排列的自然选择。 (3) 研究遗传差异的混合的基因组和表型后果 亚人群。通过对黑腹果蝇的几个混合群体进行测序，研究将确定 基因-基因相互作用在驱动不同混合种群的自然选择中的相对重要性。 此外，通过利用来自一个混合群体的表型数据，该数据已用于许多研究 关联研究，研究将评估混合物在塑造复杂表型方面的重要性 在初始基因流事件之后，开发本地祖先意识方法来绘制复杂性状 协会。