7q11.23 Syndromes Reveal BAZ1B as a Master Regulator of the Modern Human Face and Validate the Self-Domestication Hypothesis

Abstract

Symmetrical 7q11.23 dosage alterations cause craniofacial and cognitive/behavioral phenotypes that provide a privileged entry point into the evolution of the modern human face and (pro-) sociality. We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 5 7q11.23 Copy Number Variants (CNVs). Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in neural crest (NC)-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we uncover a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream 10 targets, thereby providing the first empirical validation of the self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face.One Sentence Summary: BAZ1B dosage shapes the modern human face. 15

Human Social Evolution: Self-Domestication or Self-Control?

“…There are certainly differences in human morphology as well as in genes when Neanderthals, Denisovans and anatomically modern humans are compared , and some changes are in genes affecting pathways in which neural crest cells are involved and that lead to changes in the cranium. In a recent study, Zanlella et al (2019) showed that there were changes in the chromatin remodeler BAZ1B in neural crest stem cells during the evolution of anatomically modern humans. They found that large-effect mutations in the regulatory region of this gene lead to DS-like cranial and neural disease-related variation in modern humans.…”

The Domestication of Humans

“…A crucial relevant development has been the discovery that the chromatin remodeler BAZ1B in neural stem cells controls the evolution of the modern human face [76]. Contrary to [28] and other alternatives proposed, neural stem cells are deeply involved in domestication [13].…”