Genetically identical individuals, such as human twins, are expected to be very similar, but they nonetheless exhibit substantial differences in traits and diseases throughout their lives. In controlled laboratory settings where all individuals experience the same environment, genetically identical animals also exhibit differences in important traits, including fertility and lifespan. However, why genetically identical individuals differ from each other for these traits remains incompletely understood. In addition, how non-genetic differences that arise in one generation impact subsequent generations is not well understood. This research builds upon the principal investigator’s prior work, which revealed that differences in how genes are regulated are linked to differences in fertility across genetically identical individuals and that non-genetic differences in one generation can lead to predictable differences in subsequent generations. Using a powerful set of experiments, this project will investigate how DNA and other factors interact to control differences among genetically identical individuals. This research priority will advance scientific progress in biotechnology and artificial intelligence, as well as contribute to national health, because many diseases are not just regulated by the DNA sequence alone, but by interactions with other factors. Genetically identical, i.e. isogenic, individuals exposed to the same environment can develop at different rates, grow to different sizes, and produce differing numbers of progeny. Such phenotypic variability raises key questions: 1) what drives variability across isogenic individuals in the same environment?; 2) how do populations differentially evolve when they are isogenic but epigenetically distinct?; and 3) how can phenotypes of isogenic individuals be better predicted? This research will use a highly integrated set of three objectives to answer each of these questions, all using isogenic populations within th