The Evolution of DNA Replication Timing in Great Apes

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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.