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

项目总结 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，促进寄主范围和抗药性等重要过程。尽管几十年来 在CNV研究中，关于它们的形成和动力学的许多问题仍然没有答案。由于与众不同 基因组特征，易于体外繁殖，以及CNV形成的相对简单，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迅速获得CNV。通过 研究这些CNV的连接，我们已经确定了有助于 它们在生物体中的形成；基因组中富含A/T的特征既触发DNA断裂，又便于 后续容易出错的维修。根据这一发现，我们推测P。 恶性疟原虫基因组(&gt；80%)具有高度适应性。我们的目标是探索这一点 假设使用不同的人类感染的疟原虫物种，这些物种的基因组显示出一系列AT-1基因。 含量(总体相差20%，基因间隔区相差约30%)。要做到这一点，我们将生成高度精确的 基因组组装，以表征CNV连接和导致其形成的序列。我们将确定 在体内导致DNA断裂和CNV形成的基因组特征。我们将测量 新的CNV的产生，在基础和应激条件下。这些建议的研究将有助我们 创建不同疟疾物种适应潜力的基因组图，为我们的模型提供确凿的证据 CNV的形成，并定义影响CNV演变的约束条件。这种知识，以及新的方法 在本项目期间开发的，将为开发限制基于CNV的适应的方法铺平道路 处于快速进化中的各种微生物、癌症和其他细胞类型。

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.