Human chromosome‐specific aneuploidy is influenced by DNA‐dependent centromeric features

Intrinsic genomic features of individual chromosomes can contribute to chromosome‐specific aneuploidy. Centromeres are key elements for the maintenance of chromosome segregation fidelity via a specialized chromatin marked by CENP‐A wrapped by repetitive DNA. These long stretches of repetitive DNA vary in length among human chromosomes. Using CENP‐A genetic inactivation in human cells, we directly interrogate if differences in the centromere length reflect the heterogeneity of centromeric DNA‐dependent features and whether this, in turn, affects the genesis of chromosome‐specific aneuploidy. Using three distinct approaches, we show that mis‐segregation rates vary among different chromosomes under conditions that compromise centromere function. Whole‐genome sequencing and centromere mapping combined with cytogenetic analysis, small molecule inhibitors, and genetic manipulation revealed that inter‐chromosomal heterogeneity of centromeric features, but not centromere length, influences chromosome segregation fidelity. We conclude that faithful chromosome segregation for most of human chromosomes is biased in favor of centromeres with high abundance of DNA‐dependent centromeric components. These inter‐chromosomal differences in centromere features can translate into non‐random aneuploidy, a hallmark of cancer and genetic diseases. Synopsis Intrinsic genomic features of individual chromosomes can contribute to chromosome‐specific aneuploidy. Here, DNA‐dependent centromeric features rather than centromere length are found to correlate with varying missegregation rates within human cells. Chromosome‐specific aneuploidy occurs in mitosis following centromere perturbations. Human centromeres are intrinsically heterogeneous at the level of centromeric DNA‐dependent features. Heterogeneity of human centromeric DNA determines the chromosome segregation fidelity of individual human chromosomes during mitosis. Graphical Abstract Missegregation rates vary among different chromosomes, with biased based on abundance of DNA‐dependent centromeric components rather than centromere length.