Non-Random Mis-Segregation of Human Chromosomes.


Session type:


Sarah McClelland1,Joseph Worrall2,Naoka Tamura1,Alice Mazzagatti1,Nadeem Shaikh1,Tineke van Lingen1,Bjorn Bakker3,Elina Vladimirou4,Floris Foijer3
1Barts Cancer Institute,2Barts Cancer Institute, Queen Mary University of London,3ERIBA,4UCL Cancer Institute



Recurrent patterns of chromosomal changes (aneuploidy) are widespread in cancer, miscarriage and congenital disorders. 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. Despite wide variation between human chromosomes in size, gene density, interphase nuclear territory and non-centromeric heterochromatin it is currently unknown whether these or additional characteristics generate bias in mis-segregation rates, since high-throughput methods to analyse chromosome-specific aneuploidy are lacking.


We took advantage of a new high-throughput method for measuring aneuploidy using the ImageStream cytometer, previously employed to quantify individual FISH-marked centromeres in thousands of single cells enabling detection of monosomy and trisomy in peripheral blood mononuclear cells with high accuracy. Using this system we performed the first comprehensive and systematic analysis of individual chromosome mis-segregation rates at magnitude-order higher cell number than conventional approaches, and validated these results with single cell sequencing.


We show that human chromosome mis-segregation is non-random, with a small subsets of chromosomes contributing to genome change. This implies that recurrent aneuploidy in human pathologies may be attributable in part to chromosome-specific alteration rates. Moreover, we demonstrate that established methods to elevate chromosome mis-segregation due to disruption of bipolar spindle assembly depend in part on a mitotic delay and cohesion fatigue that impacts correction of improper chromosome-spindle attachments, and acutely affects chromosomes 1 and 2.


Our findings suggest that non-random mis-segregation could act in parallel with evolutionary selection to drive recurrent aneuploidy in cancer, particularly if non-random mis-segregation operates throughout tumour development. Further characterisation of signatures of aneuploidy following different insults to mitotic fidelity may lead to the ability to infer mechanisms underlying cancer CIN by analysing the identity and behaviour of individual chromosomes prone to mis-segregation.