What makes us human? Revealing the (epi)genetic basis of the modern human brain evolution

We previously developed a technique to reconstruct the epigenetics of ancient human groups (Science 2014), which we later used to identify human adaptations (Cell 2019). Here, we will use a similar approach to uncover the adaptations that led to the modern human brain.
Many adaptations are attributed to changes in gene regulation, but such changes are difficult to identify based on DNA sequence comparisons. To understand the role of differential gene regulation in the evolution of the modern human brain and skull, we need means to reconstruct gene activity patterns in extinct archaic humans (Neanderthals and Denisovans), as direct measurement is infeasible. To identify human-specific adaptations, we will compare DNA methylation patterns between modern humans, archaic humans and nonhuman great apes. DNA methylation is a key epigenetic mark that bears ample information on patterns of gene activity. For this, we offer to use a method we developed in the past (Science 2014) to reconstruct pre-mortem DNA methylation in ancient samples, and to measure directly genome-wide DNA methylation in present-day samples.
Our labs were the first to reconstruct DNA methylation in archaic humans, as well as to experimentally generate genome-wide DNA methylation maps in human bones. We are therefore optimally positioned to carry out the proposed activities, including the generation of DNA methylation database in humans and other apes; the identification of skull- and brain-related genes that are differentially regulated; the identification of anatomical, behavioral and cognitive functions affected by these genes; and the experimental validation of these effects.
Compendium of DNA methylation maps, differentially regulated brain-related genetic networks, and submitted manuscripts and conference presentations.
We will extend our understanding of “what makes us human” by revealing the biological processes and genetic networks that led to the formation of the modern human brain.