The Fragile Breakage versus Random Breakage Models of Chromosome Evolution

For many years, studies of chromosome evolution were dominated by the random breakage theory, which implies that there are no rearrangement hot spots in the human genome. In 2003, Pevzner and Tesler argued against the random breakage model and proposed an alternative “fragile breakage” model of chromosome evolution. In 2004, Sankoff and Trinh argued against the fragile breakage model and raised doubts that Pevzner and Tesler provided any evidence of rearrangement hot spots. We investigate whether Sankoff and Trinh indeed revealed a flaw in the arguments of Pevzner and Tesler. We show that Sankoff and Trinh's synteny block identification algorithm makes erroneous identifications even in small toy examples and that their parameters do not reflect the realities of the comparative genomic architecture of human and mouse. We further argue that if Sankoff and Trinh had fixed these problems, their arguments in support of the random breakage model would disappear. Finally, we study the link between rearrangements and regulatory regions and argue that long regulatory regions and inhomogeneity of gene distribution in mammalian genomes may be responsible for the breakpoint reuse phenomenon.Synopsis: Genomes are constantly changing. If a genome is compared to a continental landform, then one type of change—point mutations—is analogous to gradual changes in the landscape due to erosion by wind and water. A second type of change—genome rearrangements—comprises evolutionary “earthquakes” that dramatically change the landscape. A fundamental question in studies of chromosome evolution is whether these earthquakes are happening along evolutionary “faults” (hot spots of rearrangements) or at “random” genomic positions. For many years, studies of chromosome evolution were dominated by the random breakage theory, which implies that there are no rearrangement hot spots in the human genome. In 2003, Pevzner and Tesler argued against the random breakage model and proposed an alternative “fragile breakage” model of chromosome evolution. In 2004, Sankoff and Trinh performed a series of computational simulations that argued against the fragile breakage model and raised doubts that Pevzner and Tesler provided any evidence of rearrangement hot spots. The authors show that Sankoff and Trinh's simulation misidentifies synteny blocks, that it does not accurately simulate what Pevzner and Tesler (2003) did, and that the parameters of Sankoff and Trinh do not reflect the realities of the comparative genomic architecture of human and mouse.