UC San Diego

A fundamental concept of molecular biology is that cellular functions are shared among all living organisms. Identifying DNA sequences that are conserved across species are generally thought as a proxy towards uncovering important cellular functions. Such proxies have not been appropriate to understand the functional consequences of epigenetic modifications, which regulate the expression of protein-coding genes. Unlike the DNA sequence, epigenetic modifications are dynamic and change depending on factors including cellular context and age. To further elucidate the importance of these epigenetic modifications towards functional effects and relationship with DNA sequence, I characterized epigenetic changes while taking into account the differing dynamics with respect to time.

In the first chapter, I asked if different life histories that yield differences in genomic architecture are also reflected in the rate of epigenomic evolutionary changes by comparing the rate of epigenemic evolution in closely related species of Drosophila and Mus musculus. I found that, despite large differences in genomic architecture, the rate of epigenetic evolution was strikingly similar, such that they reflect the molecular clock that was observed in protein evolution.

For the remainder of my thesis, I studied the changes of a particular epigenetic modification, DNA methylation, with respect to a single lifetime across species. Previous studies in humans have demonstrated that DNA methylation can be used to measure age in humans, reflecting an epigenetic clock. In the second chapter, I asked whether these changes can also measure age in mice. I found that epigenetic clocks can also measure age in mice, and that these clocks can also be slowed in long-lived mice. In my third chapter, I asked whether these changes with respect to age are conserved among mammals. For this purpose, I specifically characterized methylation changes with respect to age in conserved sequences between dogs and humans. I found that these changes were conserved and can be used to translate age across mammals.

Overall, my work characterizes the evolution of epigenetic modifications across species, which seemingly act as clocks measuring both evolutionary time and chronological age.