Role of mutation rate variation in patterns of molecular evolution in Drosophia

描述(由申请人提供)：拟议研究的长期目标是理清支配果蝇基因组进化的力量的贡献。这个项目特别关注突变率变异在果蝇分子进化模式中的作用。由于新的等位基因变异的产生是分子进化过程的第一步，了解突变率的异质性对编码序列和非编码序列进化的影响将有助于理解黑腹果蝇基因组的分子进化动力学。 为了解决这个问题，我将首先建立一个适用于DNA序列进化的中性突变模型，然后使用这个用于假设驱动检验的零模型来研究基因组功能部分的进化模式。具体地说，我建议通过研究无约束的到达即死(DOA)非长末端重复(Non-LTR)反转录转座元件的多态来表征果蝇基因组中的中性突变谱。通过比较这些序列的多态和发散谱，我可以测试这些序列是否以与中性一致的方式进化，并潜在地验证使用不受限制的序列的替代模式来推断潜在的突变过程的方法。 除了表征突变谱和验证DOA序列的中立性外，这些多态和分歧数据还可以帮助我们理解单核苷酸突变在相邻编码区和非编码区产生观察到的替代模式中的作用，因此将应用于另外两个背景。首先，我将通过比较基因组不同部分的多态和发散谱，来测试单凭突变率变异是否足以解释这种有机体中被广泛证明的替换率和模式的异质性。其次，我将使用这些来自DOA元件的多态和分歧数据来评估突变率变异和选择对黑腹果蝇基因组中相邻编码和非编码序列的进化速度的贡献。 这项拟议的研究与公共健康相关，因为这些发现将加深我们对塑造基因组进化的力量的理解，并将有助于开发工具，对昆虫、哺乳动物和病原体等各种生物的基因组进行比较功能注释。

DESCRIPTION (provided by applicant): The long-term goal of the proposed research is to disentangle the contributions of the forces that govern the evolution of the Drosophila genome. In particular, this project focuses on the role of mutation rate variation in patterns of molecular evolution in Drosophila melanogaster. Since mutational generation of novel allelic variants is the first step of the molecular evolutionary process, understanding the effects of heterogeneity in mutation rate on the evolution of coding and noncoding sequences will contribute greatly to the understanding of molecular evolutionary dynamics of the D. melanogaster genome. To address this question, I will first establish an appropriate neutral mutational model for DNA sequence evolution and then use this null model for hypothesis-driven testing to investigate patterns of evolution in functional portions of the genome. Specifically, I propose to characterize the neutral mutational spectrum in the Drosophila melanogaster genome by surveying polymorphism in unconstrained dead-on arrival (DOA) non-long-terminal-repeat (non-LTR) retrotransposable elements. By comparing the polymorphism and divergence spectra of these sequences I can test whether these sequences are evolving in a manner that is consistent with neutrality and potentially validate the approach of using substitutional patterns from unconstrained sequences to infer the underlying mutational process. Beyond characterizing the mutational spectrum and validating the neutrality of DOA sequences, these polymorphism and divergence data can inform our understanding of the role of single-nucleotide mutations in generating observed substitutional patterns at adjacent coding and noncoding regions, and will therefore be applied in two additional contexts. I will first test whether mutation rate variation alone is sufficient to explain the extensively documented heterogeneity in rates and patterns of substitution in this organism by comparing polymorphism and divergence spectra from different parts of the genome previously documented to have significantly different substitutional profiles. Second, I will use these polymorphism and divergence data from the DOA elements to evaluate the contribution of mutation rate variation and selection to rates of evolution in adjacent coding and noncoding sequences in the D. melanogaster genome. This proposed research is relevant to public health in that the findings will deepen our understanding of the forces that shape genome evolution, and will contribute to the development of tools for comparative functional annotation of genomes of organisms as diverse as insects, mammals, and pathogens.