ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Science Advances 2019;5:eaaw7908

This paper shows that the craniofacial and cognitive/behavioral phenotypes caused by alterations at the critical gene region for the Williams-Beuren syndrome is caused by changes in the chromatin remodeler BAZ1B in neural crest, and can serve as an entry point into the evolution of the modern human face and pro-sociality.

Williams-Beuren syndrome is caused by the hemi-deletion of 28 genes at the 7q11.23 region, and represents a neurodevelopmental condition whose craniofacial dysmorphisms and cognitive/behavioral traits bear directly on domestication-related traits such as facial reduction and retraction, pronounced friendliness, and reduced reactive aggression. Charles Darwin in The Descent of Man considered the analogy between modern humans and domesticated species. Anatomically, modern humans display craniofacial and prosocial behaviors that are suggestive of traits that distinguish domesticated species from their wild type. This is known as the self-domestication hypothesis: modern humans went through a domestication process during their evolution, as did cats and dogs. The so-called ‘domestication syndrome,’ with a set of domestication-related traits was proposed to result from mild neural crest deficits (1).

Here, the authors identified the BAZ1B gene at 7q11.23 as a master regulator of the modern human face, based on a molecular and functional dissection in the thus far largest cohort of Williams-Beuren syndrome patients. Then, they utilized the versatility of CRISPR-Cas9 to generate an allelic series of endogenously tagged BAZ1B across 7q11.23 dosages to define its dosage-dependent genome-wide occupancy. They defined a pivotal role for BAZ1B as an enhancer regulator, consistent with its preferential binding of distal regulatory regions, and to partition its dosage-dependent regulation into bona fide direct and indirect targets. Further on, they provide the first experimental evidence for the cardio-cephalic neural crest syndrome that had been suggested to explain the domestication syndrome and had pointed to BAZ1B as one of the candidates underlying this syndrome. It also reports a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets. Of these genes, FOXP2, ROBO1, and ROBO2 have been associated with brain wiring processes critical for vocal learning in several species.

This provides the first empirical validation of the human self-domestication hypothesis and positions BAZ1B as a master regulator of the modern human face. It is remarkable that genes implicated in neural crest development also play significant roles in cognitive processes, such as language or the theory of mind (understand of desires and intentions, among others) which are affected in the 7q11.23 syndromes.

Reference:

1. Wilkins AS, et al. The “domestication syndrome” in mammals: a unified explanation based on neural crest cell behavior and genetics. Genetics. 2014 Jul;197(3):795-808. doi: 10.1534/genetics.114.165423.