Mutations in non-coding regulatory DNA such as enhancers underlie a wide variety of diseases including developmental disorders and cancer. As enhancers rapidly evolve, understanding their function and configuration in non-human disease models can have important clinical applications. Here, we analyze enhancer configurations in tissues isolated from the common marmoset, a widely used primate model for human disease. Integrating these data with human and mouse data, we find that enhancers containing trait-associated variants are preferentially conserved. In contrast, most human-specific enhancers are highly variable between individuals, with a subset failing to contact promoters. These are located further away from genes and more often reside in inactive B-compartments. Our data show that enhancers typically emerge as instable elements with minimal biological impact prior to their integration in a transcriptional program. Furthermore, our data provide insight into which trait variations in enhancers can be faithfully modeled using the common marmoset.Modeling diseases in non-human species is complicated as many enhancers that regulate expression are species specific. Castelijns et al. demonstrate that species-specific enhancers are highly variable and poorly integrated in the regulatory network, suggesting their biological impact is low. Instead, disease-associated enhancers are typically conserved and can therefore be modeled.

chromatin conformation, enhancer, evolution, gene regulation, individual variability, marmoset,
Cell Reports
Department of Developmental Biology

Castelijns, B. (Bas), Baak, M.L. (Mirna L.), Geeven, G, Vermunt, M.W. (Marit W.), Wiggers, C.R.M. (Caroline R.M.), Timpanaro, I.S. (Ilia S.), … Creyghton, M.P. (Menno P.). (2020). Recently Evolved Enhancers Emerge with High Interindividual Variability and Less Frequently Associate with Disease. Cell Reports, 31(12). doi:10.1016/j.celrep.2020.107799