Autosomal Dosage Compensation in Aneuploidy and Cancer Involves Transcriptional Burst Regulation

Datasets This repository contains processed output data to reproduce figures and findings. Repository contains the following data: Spike-in normalised count data from single-cell Xpress-seq of aneuploid clonal cell lines, in long text R RDS format and SingleCellExperiment R RDS format. Segmented chromosome copy numbers and ploidies from DNA-seq of aneuploid clonal cell lines, in text format. Proteomics data from aneuploid clonal cell lines, in Excel and text format. Transcriptional burst kinetics inference of aneuploid clonal cell lines and fibroblasts from Reinius B et al., 2016 Nat Genet, in text format. Abstract Aneuploidy, resulting from whole-chromosome or segmental gains and losses, is generally detrimental to organismal fitness and is strongly associated with tumorigenesis. While sex chromosome aneuploidies are relatively well tolerated due to dedicated allelic dosage compensation mechanisms, the existence of comparable regulatory processes for autosomes remain debated. Here, we investigate transcriptional responses to autosomal aneuploidy and identify widespread dosage compensation across affected chromosomes. Using high-sensitivity, allele-resolved single-cell RNA sequencing of monoclonal cell expansions spanning diverse ploidies and degrees of aneuploidy, we uncover consistent transcriptional compensation of both chromosomal gains and losses. This response operates in a region-specific manner across both complete and segmental aneuploidies, revealing an unexpected flexibility in dosage regulation. We show that chromosome losses are compensated through increased transcriptional burst frequency from the remaining allele. Complementary proteomics analyses demonstrate additional buffering at the protein level, resulting in a substantial, though still incomplete, restoration of stoichiometric balance across autosomal aneuploid chromosomes for both copy number gains and losses. Analyses of cancer transcriptomes confirm that compensatory mechanisms are active in human tumours. Together, our findings establish dosage compensation as a genome-wide and dynamic response to gene dose imbalance. This mechanism extends beyond sex chromosomes, supports transcriptional homeostasis, and represents a fundamental and evolutionarily conserved mode of gene regulation active across species and in aneuploid cancer cells.