A functional dissection of the genetic circuits selected in Anatomically Modern Humans and inferred from the study of neurodevelopmental disorders

Title A functional dissection of the genetic circuits selected in Anatomically Modern Humans and inferred from the study of neurodevelopmental disorders
Acronym Brain organoids, 7q11.23 CNVs and AMHs
Website http://www.testalab.eu/
Start date 2018-10-01
End date 2022-10-03
Sponsor Marie Skłodowska-Curie Action (MSCA)
Institution University of Milan

Associated cell lines

Project Description

Copy number variants of 24-26 genes at 7q11.23 cause Williams-Beuren and 7q11.23 duplication syndromes (WBS and 7dup), a pair of neurodevelopmental disorders featuring a range of symmetrically opposite traits at the level of craniofacial morphology, cognition and behaviour. Within this genetic interval, the dosages of key transcription factors and chromatin remodelers such as GTF2I and BAZ1B have been implicated, respectively, in the cognitive/behavioural and craniofacial features of the two conditions. Importantly, these genes were also linked to core features of domestication that are also hallmarks of WBS, such as hyper-sociability and lower face retraction, both through the analysis of structural variations in hyper-sociable dogs and through our own work in human lineages. Here we build on our previous insights from iPSC-based disease modelling to advance WBS and 7dup as unique entry points for the experimental validation of the ‘self-domestication’ hypothesis. Originally proposed by Darwin, the notion that the evolution of Anatomically Modern Humans (AMH) shares salient similarities with the process of animal domestication has been subsequently refined in the hypothesis of ‘self-domestication’. Only recently however, a testable and coherent set of hypotheses has been put forth, that posits in mild neural crest deficits a unifying layer of mechanisms to account for all features of the domestication syndrome. We thus reasoned that iPSC-derived neural crest lineages and brain organoids, derived from WBS and 7dup patients, could serve to illuminate the gene regulatory circuits related to self-domestication in order to define the core set of genetic differences between AMH and archaic hominins. To this end, we combine pooled genetic screens and single cell transcriptomics with our uniquely informative cohort of WBS and 7dupASD developmental models, to experimentally test the molecular architecture underlying the evolution of the modern face, cognition and sociality.