Depletion of aneuploid cells is shaped by cell-to-cell interactions

Summary Aneuploidy, the major cause of miscarriages in humans, is pervasive in early embryos but robustly dampened during development, allowing for healthy births. Later in life, aneuploidy correlates with pathological conditions including cancer. Identification of the mechanisms underlying the elimination of aneuploid cells is relevant in development and disease. Here we generated cells carrying molecularly defined segmental monosomies and trisomies and characterized their immediate impact on cellular behavior. Our data reveal signs of out-competition of cells carrying monosomies in genomic regions devoid of previously known haploinsufficient genes. Dose-dependent effects of single genes or a discrete number of genes contribute to the observed cellular behaviors. By simultaneously inducing cells carrying monosomies and trisomies of the same genomic location, we present evidence that segmental trisomies potentiate or alleviate the negative effects of the monosomy on growth, thus revealing a key role of cell interactions in defining the in vivo elimination of aneuploid cells. Highlights Segmental monosomies cause growth impairment and are out-competed. Growth impairment relies on dose-dependent effects of single genes or a discrete number of genes. Segmental trisomies of up to 1500 genes do not have a major impact on proliferation and survival. Cell competition is modulated by the presence of cells trisomic for the same genomic region. eTOC Blurb Aneuploidy has a negative impact on the growth and proliferation of all animal cells analyzed so far. Fusari et al. unravel a role of cell interactions in defining the in vivo elimination of aneuploid cells through cell competition.