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解开支配果蝇基因组进化的力量的贡献。特别是，这个项目的重点是在果蝇的分子进化模式的突变率变化的作用。由于新等位基因变异体的突变产生是分子进化过程的第一步，因此了解突变率的异质性对编码和非编码序列进化的影响将大大有助于理解D.黑腹果蝇基因组。 为了解决这个问题，我将首先建立一个适当的中性突变模型的DNA序列进化，然后使用这个空模型的假设驱动的测试，以调查模式的基因组的功能部分的进化。具体来说，我建议的中性突变谱的特点在果蝇基因组中的多态性调查无约束的死亡到达（DOA）非长末端重复（非LTR）逆转录转座因子。通过比较这些序列的多态性和发散谱，我可以测试这些序列是否以与中性一致的方式进化，并可能验证使用来自不受约束序列的取代模式来推断潜在突变过程的方法。 除了表征突变谱和验证DOA序列的中立性之外，这些多态性和分歧数据可以告知我们对单核苷酸突变在相邻编码和非编码区产生观察到的取代模式中的作用的理解，因此将应用于两个额外的上下文。我将首先测试是否突变率的变化是足以解释广泛记录的异质性，在这种生物体的替代率和模式，通过比较多态性和分歧光谱从不同的基因组部分先前记录有显着不同的替代配置文件。其次，我将使用这些多态性和分歧的DOA元素的数据，以评估突变率的变化和选择的贡献，在相邻的编码和非编码序列的进化速度在D。黑腹果蝇基因组。 这项拟议的研究与公共卫生有关，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，并将有助于开发用于昆虫，哺乳动物和病原体等多种生物体基因组的比较功能注释的工具。

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.