The impact of chromosomal fusions on 3D genome folding and recombination in the germ line

The spatial folding of chromosomes inside the nucleus has regulatory effects on gene expression, yet the impact of genome reshuffling on this organization remains unclear. Here, we take advantage of chromosome conformation capture in combination with single-nucleotide polymorphism (SNP) genotyping and analysis of crossover events to study how the higher-order chromatin organization and recombination landscapes are affected by chromosomal fusions in the mammalian germ line. We demonstrate that chromosomal fusions alter the nuclear architecture during meiosis, including an increased rate of heterologous interactions in primary spermatocytes, and alterations in both chromosome synapsis and axis length. These disturbances in topology were associated with changes in genomic landscapes of recombination, resulting in detectable genomic footprints. Overall, we show that chromosomal fusions impact the dynamic genome topology of germ cells in two ways: (i) altering chromosomal nuclear occupancy and synapsis, and (ii) reshaping landscapes of recombination.This work was supported by the Ministry of Economy and Competitiveness (CGL2014-54317-P and CGL2017-83802-P to A.R.-H., BFU2013-47736-P and BFU2017-85926-P to M.A.M.-R. and CGL2010-15243 to J.V.) and the Agència de Gestió d’Ajuts Universitaris i de Recerca, AGAUR (DI2015 and SGR1215 to A.R-H. as well as SGR468 to M.A.M.-R.). C.V. and L.A.-G. were supported by FPI predoctoral fellowships from the Ministry of Economy and Competitiveness (BES-2015-072924 and PRE-2018-083257). L.M.-G. was supported by an FPU predoctoral fellowships from the Ministry of Science, Innovation and University (FPU18/03867). M.A.M.-R. acknowledges support by the European Research Council under the 7th Framework Program FP7/2007-2013 (ERC grant agreement 609989) and the European Union’s Horizon 2020 research and innovation program (grant agreement 676556). A.R.-H. also acknowledges support from MeioNet (BFU2015-71786-REDT)