The evolution of copy number variations in the AT-rich Plasmodium genome

富含 AT 的疟原虫基因组中拷贝数变异的进化

• 批准号: 10379458
• 负责人: Jennifer Lynn Guler
• 金额: $ 40.09万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10379458
• 关键词: AT Rich Sequence; Antimalarials; Antimicrobial Resistance; Bacteria; Biology; Blood; Cells; Characteristics; Chromosomes; Clinical; Comparative Study; Copy Number Polymorphism; DNA; Detection; Disease Progression; Drug resistance; Environment; Evaluation; Event; Evolution; Exhibits; Frequencies; Future; GC Rich Sequence; Generations; Genes; Genome; Genomic Segment; Genomics; Haploidy; Human; In Vitro; Individual; Intercistronic Region; Knowledge; Laboratories; Lead; Malaria; Malignant Neoplasms; Maps; Measures; Methods; Modeling; Mutation; Nature; Nerve Degeneration; Organism; Parasites; Pathway interactions; Pharmacotherapy; Phenotype; Physiological; Plants; Plasmodium; Plasmodium falciparum; Plasmodium falciparum genome; Plasmodium genome; Plasmodium vivax; Population; Positioning Attribute; Process; Proteins; Protozoa; Public Health; Research; Resolution; Signal Transduction; Site; Source; Stress; Testing; Time; Variant; Yeasts; asexual; base; cell type; density; emerging human pathogen; experimental study; gene function; genome-wide; improved; in vivo; microbial disease; microorganism; novel; parasite genome; pathogenic microbe; pressure; repaired; tool; tool development; tumor progression

PROJECT SUMMARY Changes in the copy number of large genomic regions, termed copy number variations or CNVs, contribute to phenotypic diversity and facilitate important processes such as host range and drug resistance. Despite decades of CNV research, many questions regarding their formation and dynamics remain unanswered. Due to distinctive genome characteristics, facile in vitro propagation, and the relative simplicity of CNV formation, Plasmodium falciparum is an exceptional model to study many aspects of CNV-based adaptation. Experimental evolution demonstrates how this haploid asexual parasite rapidly acquires CNVs in the form of tandem duplications. By studying the junctions of these CNVs, we have identified the precise genome characteristics that contribute to their formation in this organism; A/T-rich features of the genome both trigger DNA breakage and facilitate subsequent error-prone repair. Based on this finding, we hypothesize that the extreme AT content of the P. falciparum genome (>80%) specifically contributes to its highly adaptive nature. We aim to explore this hypothesis using different human-infective Plasmodium species, which have genomes exhibiting a range of AT- content (differing by >20% overall and ~30% in intergenic regions). To do so, we will generate highly accurate genome assemblies to characterize CNV junctions and the sequences that lead to their formation. We will identify genome features that contribute to DNA breakage and CNV formation in vivo. We will measure the frequency of novel CNV generation, under both basal and stressed conditions. These proposed studies will facilitate our creation of a genomic map of adaptive potential for different malaria species, provide firm evidence for our model of CNV formation, and define constraints influencing CNV evolution. This knowledge, and the novel methods developed during this project, will pave the way to developing approaches to limit CNV-based adaptation in diverse microorganisms, cancers, and other cell types under rapid evolution.

项目摘要 大基因组区域拷贝数的变化，称为拷贝数变异或CNV，有助于 表型多样性和促进重要的过程，如主机范围和耐药性。尽管几十年 CNV的研究中，许多关于其形成和动力学的问题仍然没有答案。由于独特的 基因组特征，体外繁殖容易，CNV形成相对简单，疟原虫 恶性疟原虫是研究基于CNV的适应的许多方面的特殊模型。实验进化 展示了这种单倍体无性寄生虫如何以串联复制的形式快速获得CNVs。通过 通过研究这些CNV的连接点，我们已经确定了有助于 它们在这种生物体中的形成;基因组中富含A/T的特征既触发DNA断裂，又促进 后续易出错修复。基于这一发现，我们假设，极端AT含量的P。 恶性疟原虫基因组（>80%）特别有助于其高度适应性的性质。我们的目标是探索这个 假设使用不同的人类感染疟原虫物种，其基因组显示一系列AT- 含量（总体差异>20%，基因间区域差异约30%）。为了做到这一点，我们将生成高度准确的 基因组组装来表征CNV连接和导致其形成的序列。我们将确定 基因组特征有助于体内DNA断裂和CNV形成。我们将测量 新的CNV产生，在基础和应激条件下。这些建议的研究将有助于我们 创建不同疟疾物种适应潜力的基因组图谱，为我们的模型提供了坚实的证据 CNV的形成，并定义影响CNV演变的约束条件。这些知识和新颖的方法 在本项目期间开发的，将为开发限制基于CNV的适应方法铺平道路， 各种微生物，癌症和其他细胞类型在快速进化。