There is no clear genetic etiology or convergent pathophysiology for autism spectrum disorders (ASD). Using induced pluripotent stem cell (iPSC)-derived brain organoids and single-cell transcriptomics, we modeled alterations in the formation of the forebrain between sons with ASD and their unaffected fathers in ten families. Relative to fathers, probands with macrocephaly presented an increase in dorsal cortical plate excitatory neurons (EN-DCP) to the detriment of preplate lineages, whereas normocephalic ASD probands presented an opposite decrease in EN-DCP-related gene expression. Both cohorts converged in a dysregulation of outer radial glia genes related to translation. In macrocephalic probands, an increase in progenitor self-renewal genes ID1/ID3 was coupled to a larger pool of cortical progenitors. Furthermore, changes in ID1/ID3 expression were best predictors of ASD clinical severity. We suggest that head circumference reveals a fundamental difference in etiological mechanisms of ASD rooted in alterations in progenitor fate and unbalanced excitatory cortical neuron diversity.

Mosaic mutations can be used to track cell lineages in humans. We used cell cloning to analyze embryonic cell lineages in two living individuals and a postmortem human specimen. Of 10 reconstructed postzygotic divisions, none resulted in balanced contributions of daughter lineages to tissues. In both living individuals, one of two lineages from the first cleavage was dominant across tissues, with 90% frequency in blood. We propose that the efficiency of DNA repair contributes to lineage imbalance. Allocation of lineages in postmortem brain correlated with anterior-posterior axis, associating lineage history with cell fate choices in embryos. We establish a minimally invasive framework for defining cell lineages in any living individual, which paves the way for studying their relevance in health and disease.

No abstract

Post-zygotic mosaic mutations can be used to track cell lineages in humans. By using cell cloning and induced pluripotent cell lines, we analyzed early cell lineages in two living individuals (a patient and a control), and a postmortem human specimen. Of ten reconstructed post-zygotic divisions, none resulted in balanced contributions of daughter lineages to tissues. In both living individuals one of two lineages from the first cleavage was dominant across tissues, with 90% frequency in blood. We propose that the efficiency of DNA repair contributes to lineage imbalance. Allocation of lineages in postmortem brain correlated with anterior-posterior axis, associating lineage history with cell fate choices in embryos. Recurrence of germline variants as mosaic suggested that certain loci may be particularly susceptible to mutagenesis. We establish a minimally invasive framework for defining cell lineages in any living individual, which paves the way for studying their relevance in health and disease.

No abstract