Non-Random Mis-Segregation of Human Chromosomes

Abstract

Summary Recurrent patterns of chromosomal changes (aneuploidy) are widespread in cancer. These patterns are mainly attributed 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 human chromosome mis-segregation is non-random. Merotelic kinetochore attachment induced by nocodazole washout leads to elevated aneuploidy of a subset of chromosomes, and high rates of anaphase lagging of chromosomes 1 and 2. Mechanistically, we show that these chromosomes are prone to cohesion fatigue that results in anaphase lagging upon release from nocodazole or Eg5 inhibition. Our findings suggest that inherent properties of specific chromosomes can influence chromosome mis-segregation and aneuploidy, with implications for studies on aneuploidy in human disease.