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Survival of Trypanosoma brucei depends upon switches in its protective Variant Surface Glycoprotein (VSG) coat by antigenic variation. VSG switching occurs by frequent homologous recombination, which is thought to require locus-specific initiation. Here, we show that a RecQ helicase, RECQ2, acts to repair DNA breaks, including in the telomeric site of VSG expression. Despite this, RECQ2 loss does not impair antigenic variation, but causes increased VSG switching by recombination, arguing against models for VSG switch initiation through direct generation of a DNA double strand break (DSB). Indeed, we show DSBs inefficiently direct recombination in the VSG expression site. By mapping genome replication dynamics, we reveal that the transcribed VSG expression site is the only telomeric site that is early replicating – a differential timing only seen in mammal-infective parasites. Specific association between VSG transcription and replication timing reveals a model for antigenic variation based on replication-derived DNA fragility. DOI: http://dx.doi.org/10.7554/eLife.12765.001, eLife digest The African trypanosome, Trypanosoma brucei, is a parasite that is transmitted between mammals by the tsetse fly, and causes a disease known as sleeping sickness in humans. Like many other parasites, trypanosomes have evolved ways to avoid being killed by their hosts. One such survival strategy involves the parasites constantly changing the molecules that coat their surface, which are the main targets recognized by their hosts’ immune systems. Switching one coat protein for another similar protein, a process called antigenic variation, allows a parasite to evade an attack and establish a persistent infection. Antigenic variation also makes it almost impossible to develop a vaccine that will offer lasting protection against the parasite. Previous research suggested that a trypanosome might deliberately break its own DNA and then exploit a repair process to switch its current coat protein-encoding gene for another one located elsewhere within its genetic material. Devlin, Marques et al. now reveal that it is unlikely that trypanosomes use a specific enzyme to break DNA deliberately during coat switching. Instead, experiments using whole-genome sequencing suggest that coat-gene-switching might arise from the strategies trypanosomes use to copy their genetic material during cell division. These findings bring researchers closer to understanding how trypanosomes start antigenic variation in order to evade their hosts’ immune responses. In addition, the findings suggest a new model that could help researchers answer an important question: how does the timing of genome copying vary from cell to cell? Nevertheless, the hypothesis proposed by Devlin, Marques et al. will now require rigorous testing. Future studies could also ask if other parasites use similar strategies to survive being attacked by their host’s immune systems. DOI: http://dx.doi.org/10.7554/eLife.12765.002