Figure 5.
Cell lines in the pooled differentiation displayed common outlier behavior in cell type composition
(A) Most of the outlier cell lines showed an excess of a particular cell type throughout the differentiation, except for some lines with a reduced population of astrocytes and progenitors at day 11.
(B) Upper: On average, each outlier line showed 2.21 outlier events per differentiation, but less than 1 event per time point (bars, 95% CI). Also, most of the lines displayed the outlier behavior either simultaneously at days 30 and 52 (young and mature stage), or just at day 11 (progenitor stage); lower: Lines with at least one abnormal cell type abundance throughout the differentiation (outlier event) showed a significant reduction in the somatic burden of acquired mutation in vitro than non-outliers (total burden, p = 3.6 · 10−3; deleterious, p = 2.7 · 10−3; Wilcoxon rank-sum test). Boxplot whiskers are within the 1.5 IQR value. See also Figure S5A.
(C) The mean proliferation rate per line (day 52/day 0) was higher in outlier lines than in non-outlier lines (p = 9.68 · 10−4, logistic regression). Boxplot whiskers are within the 1.5 IQR value.
(D) Upper: Z score correlation of gene expression (i.e., KMT2D) and cell type proportions of floor-plate progenitors type 1 (FPP-1) and neuroblasts committing to dopaminergic neurons (DA) at day 11. Each dot is an iPSC line; lower: The distribution of Pearson correlation coefficients for all genes expressed in previous cell types at day 11. See also Figure S5B.
(E) The abundance of progenitor populations was associated with the expression of genes in developmental disorder (DD) and cancer-associated (Cosmic-Tier1) genes, and to a lesser extent in adult-onset neurodegenerative disorder genes. In schizophrenia, the association is only observed with genes expressed in neurons and no enrichment is observed for non-brain disorders (hypergeometric test for overrepresentation, Benjamini-Hochberg multiple-test correction). Significance levels: pAdj >0.05 (ns, yellow), pAdj <0.05 (∗, golden yellow), pAdj <0.01 (∗∗, orange), pAdj <0.001 (∗∗∗, red).