Dosage analysis of the 7q11.23 Williams region identifies BAZ1B as a major human gene patterning the modern human face and underlying self-domestication
We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest (NC) stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 copy number variants. Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in NC-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we found a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the human self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face. In so doing, we provide experimental evidence that the craniofacial and cognitive/behavioral phenotypes caused by alterations of the Williams-Beuren syndrome critical region can serve as a powerful entry point into the evolution of the modern human face and prosociality. ; This work was funded by the Telethon Foundation (grant number GGP14265 to G.T. and G.M.), the EPIGEN Flagship Project of the Italian National Research Council (to G.T.), the European Research Council (consolidator grant number 616441-DISEASEAVATARS to G.T.), the Horizon 2020 Innovative Training Network EpiSyStem (to G.T.), Ricerca Corrente granted by the Italian Ministry of Health (to G.T. and G.M.) Giovani Ricercatori granted by the Italian Ministry of Health (to G.T.), Daunia Plast (to G.M.), Fondazione Umberto Veronesi (to P.-L.G.), the Foundation IEO-CCM (fellowship to A.V.), the Spanish Ministry of Economy and Competitiveness/FEDER funds (grant FFI2016-78034-C2-1-P to C.B.), the Generalitat de Catalunya (grant 2017-SGR-341 to C.B. and doctoral fellowships to T.O. and S.S.), the MEXT/JSPS Grant-in-Aid for Scientific Research on Innovative Areas 4903 [Evolinguistics: JP17H06379 (C.B.; PI: K. Okanoya)], a Marie Curie International Reintegration Grant from the European Union (PIRG-GA-2009-256413 to C.B.), the European Social Fund (grant BES-2017-080366 to A.A.), and the Portuguese Foundation for Science and Technology (PhD grant number SFRH/BD/131640/2017 to P.T.M.). M.Z., A.V., A.S., and S.T. conducted this study as fulfillment of their Ph.D. within the European School of Molecular Medicine (SEMM), Milan, Italy. ; Peer reviewed