Evolutionary inference with interlocus gene conversion

在人类和许多其他物种中，基因组的大部分由重复的DNA序列组成，这些重复序列通过复制而产生。当后代从只有一个拷贝的父母那里继承了DNA序列的两个拷贝时，就会发生基因复制；这些在基因组中重复的区域称为重复。在重复事件发生后，由于影响一个重复但不影响其他重复的突变，这些重复随后可能会发生分歧。然而，这种差异可以部分或完全被称为基因座间基因转换(IGC)的现象抵消。IGC通过将序列延伸从一个重复拷贝复制到另一个拷贝的相应区域来增加重复序列的相似性。IGC突变在塑造重复基因组区域如何随时间进化中所起的作用还知之甚少。该项目旨在开发统计方法，以量化和纳入IGC在塑造基因组方面的影响。通过这样做，这项研究将阐明塑造基因组中重复区域的力量，并将有助于理解这些区域的生物功能。项目目标将在本科生研究人员的协助下完成。这些学生将有机会访问东京大学的合作者，进行跨文化交流。此外，还将创建可视化工具，同时向公众传授统计推断和塑造基因组的力量。将开发和评估各种基于可能性的统计工具，用于研究IGC。一个目标是了解免疫球蛋白在不同生物物种和不同基因之间的差异。重点将放在IGC如何受到全基因组和串联复制的影响。这项研究将调查在IGC活动期间，是否有一些重复副本成为捐赠者的倾向，而另一些重复副本是否有成为接受者的趋势。将仔细考虑如何使IGC在阳性多样化选择的检测、分歧时间估计和祖先序列重建中发挥作用。这项工作将结合使用模拟和经验数据的理论开发、软件实施和测试。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

In humans and many other species, a majority of the genome consists of repeated DNA sequences that arose via duplications. A genetic duplication can occur when an offspring inherits two copies of a DNA sequence from a parent who only has one copy; these duplicated regions in the genome are called repeats. Following duplication events, these repeats can subsequently diverge due to mutations that affect one repeat but not others. However, this divergence can be partially or completely counteracted by a phenomenon known as interlocus gene conversion (IGC). IGC increases the similarity of repeated sequences by copying sequence stretches from one repeat copy into the corresponding region of another. The role of IGC mutations in shaping how repeated genomic regions evolve through time is poorly understood. This project aims to develop statistical methods for quantifying and incorporating the impact that IGC has in shaping genomes. By doing so, this research will illuminate the forces that shape repeated regions in genomes and will assist in understanding the biological function of these regions. Project goals will be accomplished with the assistance of undergraduate researchers. These students will have the opportunity to visit collaborators at the University of Tokyo in a cross-cultural exchange. In addition, visualizations will be created to simultaneously teach the general public about statistical inference and the forces that shape genomes.A variety of likelihood-based statistical tools for studying IGC will be developed and assessed. One goal is to learn how IGC varies among biological species and among genes. A focus will be on how IGC is influenced by whole genome versus tandem duplication. The research will investigate whether there are tendencies of some repeat copies to be donors and other repeat copies to be recipients during IGC events. Careful consideration will be made of how to accommodate IGC in detection of positive diversifying selection, divergence time estimation, and ancestral sequence reconstruction. The work will combine theoretical development, software implementation, and testing using a combination of simulation and empirical data.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.