Elucidating the evolutionary mode of binding site gain at novel loci

描述（由申请人提供）：影响基因表达的基因组变化可能对新形态性状的进化产生重大影响，并在癌症等疾病中发挥重要作用。虽然许多努力已经致力于定义网络的共调节基因，相对较少的是已知的相对重要性的过程中，导致招聘的基因表达调控新的和以前未结合的基因组内的位置。果蝇的neo-X染色体代表了研究这些过程的理想系统。这条染色体很年轻（约1 MYA），但已经能够招募一种调节复合物，该复合物将整个男性X染色体的基因表达水平上调两倍。这个过程被称为剂量补偿，特别是在男性中发生，以补偿他们缺失的X染色体（例如XY与XX）。近缘种D.米兰达将用于鉴定导致neo-X染色体上剂量补偿复合物结合位点进化的突变途径。通过这种分析，将有可能确定结合基序在基因组中的新位置进化的各种机制的相对重要性，包括从前位点或随机序列的从头进化，从其他基因组位置的转座，或弱结合位点的局部扩增。此外，野生D.米兰达细胞系将被分析，以确定这些结合位点是否在正选择下进化，这对Y染色体变性过程有影响。 公共卫生相关性：该研究项目旨在了解基因表达调控的基本原理。该项目的结果将与治疗和诊断由基因表达调节不当引起的人类疾病有关，如贫血和多种癌症。

DESCRIPTION (provided by applicant): Genomic changes that influence gene expression can have significant impacts on the evolution of novel morphological traits and play important roles in diseases such as cancer. While much effort has been dedicated towards defining networks of co-regulated genes, comparatively little is known about the relative importance of processes that result in the recruitment of gene expression regulators to novel and previously unbound locations within the genome. The neo-X chromosome of Drosophila miranda represents an ideal system for studying such processes. This chromosome is young (~1 MYA) yet is already capable of recruiting a regulatory complex which up-regulates gene expression levels across the entire male X chromosome by a factor of two. This process is known as dosage compensation and occurs specifically in males to compensate for their missing X chromosome (e.g. XY versus XX). Genome assemblies from close relatives of D. miranda will be used to identify the mutational path leading to the evolution of the dosage compensation complex binding sites on the neo-X chromosome. From this analysis, it will be possible to determine the relative importance of the various mechanisms by which a binding motif evolves at a novel location in the genome, including de novo evolution from a pre-site or random sequence, transpositions from other genomic locations, or the local amplification of weak binding sites. In addition, polymorphism data from wild D. miranda lines will be analyzed to determine if these binding sites evolved under positive selection, which has implications for the process of Y chromosome degeneration. PUBLIC HEALTH RELEVANCE: This research project seeks to understand basic principles underlying the regulation of gene expression. The results of this project will be relevant to the treatment and diagnosis of human diseases caused by improper regulation of gene expression such as anemia and many types of cancer.