Testing Models of Centromere Drive

智力优势：着丝粒是哺乳动物每一条染色体上的位点，在细胞分裂过程中，着丝粒组装和纺锤体附着发生在着丝粒上。每一条染色体的忠实分离依赖于着丝粒的正常功能，而纺锤体附着前后一连串事件的错误会导致染色体丢失--这是一种灾难性的遗传命运。本研究旨在了解哺乳动物着丝粒内发现的功能模块。一个被称为分子驱动的遗传过程被认为是一个物种中所有个体的着丝粒DNA高度相似的原因，而一个被称为遗传冲突的逆过程可能是物种之间发现的着丝粒卫星序列套件差异巨大的原因。因此，当卫星DNA阵列在染色体上扩展时，它们可以在雌性减数分裂期间吸引更多的微管，并导致一个亲本染色体相对于另一个亲本染色体的不平等传递。在最近提出的一个模型中，这个过程被称为着丝粒驱动，导致着丝粒结合蛋白的快速进化，这些蛋白被选择来平衡减数分裂期间每条染色体的传递，确保所有染色体在种群中平等遗传。目前的着丝粒进化模型预测，在一个给定的物种组中，不同但密切相关的物种将经历卫星序列的转移和扩展，这将导致在着丝粒上的物种特异性卫星序列。袋鼠和沙袋鼠物种的进化史有据可查，沿着已知的染色体互补物的进化史，这为直接检验着丝粒驱动假说提供了理想的机会，而不是目前支持这一理论的推理研究。这样做，着丝粒的功能组件，促进平等的染色体分离将被揭露。该项目将确定卫星DNA相互作用蛋白质是否与卫星序列套件一致进化，如着丝粒驱动所预测的那样，或者与物种趋异，如着丝粒漂移和分子驱动所预测的那样。固有的这项研究将努力，以确定是否提出的冲突驱动的这些组件的演变是负责混合不兼容性和哪些组件在细胞中的驱动器的主题。更广泛的影响：这项研究涉及广泛的参与者，包括访问教师，研究生，本科生和高中学生从各种社会经济背景的纽约，康涅狄格州，马萨诸塞州和罗得岛地区。本科独立学习的学生和就读于康州大学导师连接高中学生将积极参与整个研究。此外，这项研究将作为开发三个模块格式课程的基础，以提供利用大规模并行测序技术的培训，该技术已经彻底改变了基因组生物学，但在很大程度上仍然无法进入个人科学家。 学生将学习准备测序库，在SOLiD测序平台上进行测序，并使用生物信息学分析所得数据。该课程将向高级本科生，研究生，博士后和访问高中教师开放，作为应用遗传学和技术中心专业科学硕士课程的一部分。将高中教师纳入参与者是本研究更广泛目标的一部分，该研究旨在使教育工作者能够培训未来几代科学家以及未来将受到基因组技术转变直接影响的普通公众中的非科学家成员。

Intellectual Merit: Centromeres are the site on every chromosome of mammals where kinetochore assembly and spindle attachment occur during cell division. Faithful segregation of every chromosome relies on the proper functioning of centromeres, and errors in the cascade of events prior to and after spindle attachment lead to chromosome loss - a disastrous genetic fate. This research aims to understand the functional modules found within mammalian centromeres. A genetic process called molecular drive is thought to account for the observation that the DNA found at centromeres across all individuals within one species is highly similar, whereas a counter process called genetic conflict may be responsible for the observation that vastly different centromere satellite sequence suites are found between species. Accordingly, as satellite DNA arrays expand on a chromosome, they can attract more microtubules during female meiosis and lead to unequal transmission of one parental chromosome over the other. In a recently proposed model, this process, called Centromere Drive, results in the rapid evolution of centromere binding proteins selected to equalize the transmission of each chromosome during meiosis, ensuring all chromosomes are inherited equally in a population. Current models of centromere evolution and predict that different, but closely related species within a given species group would experience shifts and expansions of satellite sequences that would result in species-specific satellite sequences at centromeres. The well-documented evolutionary history of species of kangaroos and wallabies, along with the known history of the evolution of their chromosome complements, provides an ideal opportunity to test the Centromere Drive hypothesis directly, as opposed to the inferential studies that currently support this theory. In doing so, the functional components of centromeres that facilitate equal chromosome segregation will be uncovered. This project will determine whether satellite DNA interacting proteins evolve in concert with satellite sequence suites, as predicted by centromere drive, or with species divergence, as predicted by centromere drift and molecular drive. Inherent to this research will be efforts to determine whether the proposed conflict driven evolution of these components are responsible for hybrid incompatibilities and which components in the cell are the subject of drive. Broader impacts: This research involves a broad range of participants, including visiting faculty, post-graduate, undergraduate and high school students from a variety of socioeconomic backgrounds in the New York, Connecticut, Massachusetts and Rhode Island area. Undergraduate independent study students and high school students enrolled in the UConn Mentor Connection will be active participants throughout this research. Moreover, this research will serve as the foundation for development of three modular-format courses to provide training in utilization of massively parallel sequencing technology, which has revolutionized genome biology, but remains largely inaccessible to the individual scientist. Students will learn to prepare a library for sequencing, perform sequencing on the SOLiD sequencing platform and use bioinformatics to analyze the resulting data. The course will be open to advanced undergraduates, graduate students, postdocs and visiting high school teachers as part of the Professional Science Masters program in the Center for Applied Genetics and Technology. The inclusion of high school teachers as participants is part of the broader goals of this research in empowering educators to train both future generations of scientists as well as the future nonscientist members of the general public that will be directly impacted by shifts in genomic technologies.