We tackle the limitations described above by merging several cutting-edge approaches, primarily human-ape hybrid cells, and massively parallel reporter assays (MPRAs). Hybridizing human cells with ape cells allows us to generate a shared nuclear environment, where environmental and trans effects are well-controlled. Thus, in these hybrid cells, differences in gene regulation between the species can only be attributed to divergence in cis-regulation, and these cells serve as a powerful tool to map the gamut of cis-regulatory expression changes separating humans from other apes.
In parallel, we employ MPRAs to measure the regulatory function of each of the variants that distinguish humans from their closest extinct and extant relatives – Neanderthals, Denisovans, and other non-human apes. The combination of human-ape hybrids with MPRAs is particularly synergistic, as the hybrids provide a catalog of the cis-regulatory gene expression changes that emerged in human evolution, and the MPRAs provide the sequence variants that drove these expression changes.
To expand the power of MPRAs, we also develop a new MPRA, where the regulatory effects of changes in DNA methylation can be studied en masse. We apply this method to investigate how each of the DNA methylation changes that separates modern humans from Neanderthals and Denisovans have affected gene expression. Given the lack of gene regulatory data on our extinct relatives due to rapid post-mortem degradation, this method provides a unique glimpse into the regulatory mechanisms that shaped gene expression in extinct lineages.
Finally, we combine the methods above with in vitro and in vivo phenotyping to identify the specific genetic changes that drove human adaptations, but also propelled the emergence of human-specific diseases. Overall, our lab aims to leverage and develop cutting-edge genetic approaches in order to shed light on the gene regulatory changes that made us human. Below, I detail our key research directions and achievements since June 2021, when I opened my lab at the Weizmann Institute. Finally, I will lay out some broad directions that I will be interested in pursuing in the future.
