Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Genetics
First Advisor
Noonan, James
Abstract
Enhancers play a crucial role in specifying when and where genes are expressed, and changes in their function have been shown to influence trait evolution. However, it remains challenging to determine the sequence features that contribute to variation in enhancer function across species. Here I assessed the contribution of orphan CpG islands (oCGIs), which are intronic and intergenic regions enriched in CpG dinucleotides, to enhancer evolution. I identified oCGIs in nine mammalian species and integrated them with maps of enhancer activity-associated histone modifications (H3K27ac, H3K4me3, H3K4me2, and H3K4me1), finding that active enhancers are overrepresented at oCGIs. I found widespread turnover in oCGIs across species, even in ancient, conserved enhancers. The species-specificity of oCGIs is predictive of the species-specificity of enhancer activity across many adult and developing tissues. I found that species-specific active oCGIs are correlated with higher gene expression of nearby genes. oCGIs may be especially relevant to Human Gain Enhancers, a class of enhancers with gained function in the developing human brain compared to rhesus and mouse. Using a humanized mouse model, I examined in detail one enhancer which contains an oCGI in human but not in mouse. I found that the human enhancer showed a gain of activity compared to its mouse ortholog in the developing diencephalon, and that this gain overlapped the human oCGI. Finally, I demonstrated that oCGIs predict the binding of transcription factors with a variety of motif attributes. Based on these results, I propose a model for how oCGI turnover contributes to the evolution of enhancers.
Recommended Citation
Kocher, Acadia, "CpG Island Turnover Predicts Evolutionary Change in Enhancer Activity" (2023). Yale Graduate School of Arts and Sciences Dissertations. 955.
https://elischolar.library.yale.edu/gsas_dissertations/955
