The rise and fall of breakpoint reuse depending on genome resolution

BACKGROUND: During evolution, large-scale genome rearrangements of chromosomes shuffle the order of homologous genome sequences ("synteny blocks") across species. Some years ago, a controversy erupted in genome rearrangement studies over whether rearrangements recur, causing breakpoints to be reused. METHODS: We investigate this controversial issue using the synteny block's for human-mouse-rat reported by Bourque et al. and a series of synteny blocks we generated using Mauve at resolutions ranging from coarse to very fine-scale. We conducted analyses to test how resolution affects the traditional measure of the breakpoint reuse rate. RESULTS: We found that the inversion-based breakpoint reuse rate is low at fine-scale synteny block resolution and that it rises and eventually falls as synteny block resolution decreases. By analyzing the cycle structure of the breakpoint graph of human-mouse-rat synteny blocks for human-mouse and comparing with theoretically derived distributions for random genome rearrangements, we showed that the implied genome rearrangements at each level of resolution become more “random” as synteny block resolution diminishes. At highest synteny block resolutions the Hannenhalli-Pevzner inversion distance deviates from the Double Cut and Join distance, possibly due to small-scale transpositions or simply due to inclusion of erroneous synteny blocks. At synteny block resolutions as coarse as the Bourque et al. blocks, we show the breakpoint graph cycle structure has already converged to the pattern expected for a random distribution of synteny blocks. CONCLUSIONS: The inferred breakpoint reuse rate depends on synteny block resolution in human-mouse genome comparisons. At fine-scale resolution, the cycle structure for the transformation appears less random compared to that for coarse resolution. Small synteny blocks may contain critical information for accurate reconstruction of genome rearrangement history and parameters.