Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Models of evolution by genome rearrangements are prone to two types of flaws: One is to ignore the diversity of susceptibility to breakage across genomic regions, and the other is to suppose that susceptibility values are given. Without necessarily supposing their precise localization, we call "solid" the regions that are improbably broken by rearrangements and "fragile" the regions outside solid ones. We propose a model of evolution by inversions where breakage probabilities vary across fragile regions and over time. It contains as a particular case the uniform breakage model on the nucleotidic sequence, where breakage probabilities are proportional to fragile region lengths. This is very different from the frequently used pseudouniform model where all fragile regions have the same probability to break. Estimations of rearrangement distances based on the pseudouniform model completely fail on simulations with the truly uniform model. On pairs of amniote genomes, we show that identifying coding genes with solid regions yields incoherent distance estimations, especially with the pseudouniform model, and to a lesser extent with the truly uniform model. This incoherence is solved when we coestimate the number of fragile regions with the rearrangement distance. The estimated number of fragile regions is surprisingly Small, suggesting that a minority of regions are recurrently used by rearrangements. Estimations for several pairs of genomes at different divergence times are in agreement with a slowly evolvable colocalization of active genomic regions in the cell.8514271439FAPESP [2013/25084-2]French Agence Nationale de la Recherche (ANR) [ANR-10-BINF-01-01]ICT FP7 european programme EVOEVOFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)