Single cell transcriptome in aneuploidies reveals mechanisms of gene dosage imbalance

Aneuploidy is a major source of gene dosage imbalance due to copy number alterations (CNA) and viable human trisomies are model disorders of altered gene expression. We studied gene and allele specific expression (ASE) of 9668 single-cell fibroblasts from T21 discordant twins and from mosaic T21, T18, T13 and T8. We examined 928 single cells with deep scRNAseq. Expected and observed overexpression of trisomic genes in trisomic vs. diploid bulk RNAseq was not detectable in trisomic vs. diploid single cells. Instead, for trisomic genes with low-to-average expression, their altered gene dosage was mainly due to the higher fraction of trisomic cells simultaneously expressing these genes, in agreement with a stochastic 2-state burst-like model of transcription. These results, confirmed in a further analysis of 8740 single fibroblasts, suggest that the specific transcriptional profile of each gene contributes to the phenotypic variability of trisomies. We propose an improved model to understand the effects of CNA and, more generally, of gene regulation on gene dosage imbalance. Overall design: Single-cell RNA seq study on 9668 human fibroblasts in different Trisomies, in order to investigate gene dosage imbalance mechanisms. This study make use of some data already published in GSE123028 (mosT18, mosT8 and most of twins) and newly produced data (mos13, mos21). the processed.data file contains the processing of all trisomies in the context of the new manuscript. See README.txt below.