Origins of chromosome instability unveiled by coupled imaging and genomics
Marco Raffaele Cosenza, Alice Gaiatto, Büşra Erarslan Uysal, Álvaro Andrades, Nina Luisa Sautter, Marina Simunovic, Michael Jendrusch, Sonia Zumalave, Tobias Rausch, Aliaksandr Halavatyi, Eva‐Maria Geissen, Joshua Eigenmann, Thomas Weber, Patrick Hasenfeld, Eva Benito, Catherine Brasseur, Isidro Cortés‐Ciriano, Andreas E. Kulozik, Rainer Pepperkok, Jan O. Korbel
Abstract
, the underlying processes and rates of spontaneous CA formation in human cells are underexplored. Here we introduce machine-learning-assisted genomics and imaging convergence (MAGIC)-an autonomously operated platform that integrates live-cell imaging of micronucleated cells, machine learning on-the-fly and single-cell genomics to systematically investigate CA formation. Applying MAGIC to near-diploid, non-transformed cell lines, we track de novo CAs over successive cell cycles, highlighting the common role of dicentric chromosomes as initiating events. We determine the baseline CA mutation rate, which approximately doubles in TP53-deficient cells, and observe that chromosome losses arise more frequently than gains. The targeted induction of DNA double-strand breaks along chromosome arms triggers distinct CA processes, revealing stable isochromosomes, coordinated segregation and amplification of isoacentric segments in multiples of two, as well as complex CA outcomes, influenced by the chromosomal break location. Our data contrast de novo CA spectra from somatic mutational landscapes after selection occurred. The experimentation enabled by MAGIC advances the dissection of DNA rearrangement processes, shedding light on fundamental determinants of chromosomal instability.