Periodic Reporting for period 1 - RegEvoHum (Studying the cis-regulatory changes that have shaped human evolution)
Berichtszeitraum: 2023-02-01 bis 2025-07-31
In the animal kingdom, many human adaptations stand out. Our brain size has increased by 3-fold, we have transitioned to upright walking, and our learning period has become particularly long. These adaptations were pivotal to our success as a species, but they also brought with them new diseases, including Alzheimer’s disease, epithelial cancers, preterm labor and more. How did this process occur? How did we become human? and why did these extraordinary adaptations come with such a high price tag?
Gene regulatory changes (i.e. changes to the level, timing, and tissues in which a gene is expressed) are thought to be the main drivers of evolution. However, our understanding of how gene regulatory changes shape human evolution is limited. In our lab, we study how gene regulatory changes have differentiated us from our closest relatives: the extinct Neanderthals and Denisovans, and the extant great apes. We use and develop a wide range of tools and resources, both computational and experimental.
Gene regulatory changes (i.e. changes to the level, timing, and tissues in which a gene is expressed) are thought to be the main drivers of evolution. However, our understanding of how gene regulatory changes shape human evolution is limited. In our lab, we study how gene regulatory changes have differentiated us from our closest relatives: the extinct Neanderthals and Denisovans, and the extant great apes. We use and develop a wide range of tools and resources, both computational and experimental.
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.
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.
We generated the first catalog of how each of the single-nucleotide changes that separate humans from other great apes have affected our gene expression. In parallel, we generated human-gorilla hybrid cells, which serve to identify true human-specific changes in gene expression.