Single-cell whole genome sequencing data to determine chromosome mis-segregation events

Recurrent patterns of chromosomal changes (aneuploidy) are widespread in cancer. These patterns are ascribed to selection processes due to an assumption that human chromosomes carry equal chance of being mis-segregated into daughter cells when fidelity of cell division is compromised. Human chromosomes vary widely in size, gene density and other parameters that might generate bias in mis-segregation rates, however technological limitations have precluded a systematic and high throughput analysis of chromosome-specific aneuploidy. Here, using fluorescence In-Situ hybridization (FISH) imaging of specific centromeres coupled with high-throughput single cell analysis, as well as single-cell sequencing we show that aneuploidy is non-random following a common treatment to elevate chromosome mis-segregation. Merotelic kinetochore attachment induced by temporary spindle disruption followed by washout leads to elevated mis-segregation and aneuploidy of a subset of chromosomes, particularly affecting chromosomes 1 and 2. Unexpectedly we find that a short period of mitotic delay inherent in the washout treatment is responsible for both high rates of lagging and the bias towards chromosomes 1 and 2. Mechanistically we show that these chromosomes are prone to cohesion fatigue that is exacerbated with delay in mitosis, and elevates merotelic attachment and anaphase lagging. Cohesion fatigue and biased mis-segregation of chromosomes 1 and 2 can be ameliorated by depletion of the negative regulator of cohesion, Wapl. Our findings demonstrate that inherent properties of individual chromosomes can influence chromosome mis-segregation and aneuploidy rates, with implications for studies on aneuploidy in human disease.