The Evolution of DNA Replication Timing in Great Apes

虽然人类和我们最近的灵长类亲戚（如黑猩猩）在基因水平上有99%的相同，但显然有许多不同的特征，如认知能力、语言、直立姿势等等。这个项目将探索一种有助于解释这些差异的遗传机制：DNA复制时间的变化。这个项目将测量许多人类、黑猩猩和其他类人猿染色体上DNA复制的进展。随后，该项目将识别差异，重建它们的进化轨迹，并将DNA复制变异与突变率、基因表达以及可能的新性状进化联系起来。作为该项目的社会影响的一部分，结果将传播给当前和未来的资深本科生，这一群体在一流大学中代表性不足。退伍军人对STEM领域有很高的兴趣，但往往没有同样的机会从事生物研究。该研究还将涉及本科生和研究生，并将开发一个可访问的平台，用于将该项目产生的计算数据可视化，这些数据将与研究人员和公众广泛共享。DNA是根据被称为DNA复制定时程序的定义时间顺序进行复制的。DNA复制时间与基因调控接口，并影响突变率和模式。因此，它有可能以不同寻常的方式影响进化。另一方面，我们对DNA复制时间本身是如何进化的知之甚少。该项目将利用全基因组DNA测序技术，测量大约100个人类、黑猩猩和其他类人猿基因组的DNA复制时间。生成的复制时间数据将用于识别变异，推断它们的进化模式和遗传基础，并将它们与人类特有的分子和表型性状联系起来。已知自人类-黑猩猩分化以来进化的基因将专门研究复制时间变异，以及基于复制时间分化模式确定的其他候选基因。反过来，类人猿之间的复制时间变化模式将用于推断复制时间进化的动力学，包括DNA复制起源的出生和死亡，以及DNA复制时间的变化。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The evolution of DNA replication timing in great apesAlthough humans and our closest primate relatives (e.g., chimpanzees) are ~99% identical at the genetic level, there are clearly many differing traits, such as cognitive abilities, language, upright posture, and many more. This project will explore one genetic mechanism that could help explain those differences: the variation in the timing of DNA replication. This project will measure the progression of DNA replication across the chromosomes of many humans, chimpanzees, and other great apes. Subsequently, the project will identify differences, reconstruct their evolutionary trajectory, and link DNA replication variation to mutation rates, gene expression and possibly, the evolution of new traits. As part of the societal impact of the project, results will be disseminated to current and prospective veteran undergraduate students, a group which is under-represented in leading universities. Veterans have a high interest in STEM fields but often do not have the same opportunities to engage in biological research. The research will additionally involve undergraduate and graduate students and will develop an accessible platform for visualization of the computational data generated in this project, which will be widely shared with researchers and the public. DNA is replicated according to a defined temporal order referred to as the DNA replication timing program. DNA replication timing interfaces with gene regulation and influences mutation rates and patterns. As a result, it holds the potential of affecting evolution in non-trivial ways. On the other hand, we know very little about how DNA replication timing has itself evolved. This project will measure DNA replication timing across the genomes of ~100 humans and chimpanzees as well as other great apes, using whole-genome DNA sequencing. The generated replication timing data will be used to identify variations, infer their evolutionary patterns and genetic basis, and link them to human-specific molecular and phenotypic traits. Genes that are known to have evolved since human-chimpanzee divergence will be specifically studied for replication timing variations, and other candidate genes identified based on replication timing divergence patterns. Reciprocally, patterns of replication timing variation among great apes will be used to infer the dynamics of replication timing evolution, including the birth and death of DNA replication origins, and changes in DNA replication timing.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.