Dosage responses of aneuploid autosomal chromosomes

Abstract

Aneuploidy, resulting from segmental or complete chromosomal losses or gains, is generally detrimental to organismal fitness, but is also associated with tumourigenicity. While sex chromosome aneuploidies are well-tolerated due to dedicated allelic dosage compensation mechanisms, the existence of similar regulatory processes for autosomes remains debated. Here, we investigate transcriptional responses to autosomal aneuploidies and find evidence for global dosage compensation across aneuploid chromosomes. Using high-sensitivity, allele-resolved single-cell RNA-seq on monoclonal cell expansions with varying ploidies and degrees of autosomal aneuploidy, we uncover consistent transcriptional compensation upon chromosome losses via increased burst frequency from the remaining allele. This operates in a region-specific manner across both complete and segmental aneuploidies, revealing a previously underappreciated flexibility of dosage response. Complementary proteomics analyses demonstrate additional dosage buffering at the protein level, resulting in near-stoichiometric rebalancing across autosomal aneuploid chromosomes. Analyses of cancer transcriptomes confirms that compensatory mechanisms are active in primary tumours. Our findings reveal extensive dosage compensation as a genome-wide, dynamic, response to gene product imbalance. This mechanism extends beyond sex chromosomes, supports transcriptional homeostasis, and represents a fundamental, evolutionarily conserved mode of transcriptional regulation active across species and in aneuploid cancer cells.