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

Are There Rearrangement Hotspots in the Human Genome?

In a landmark paper, Nadeau and Taylor [18] formulated the random breakage model (RBM) of chromosome evolution that postulates that there are no rearrangement hotspots in the human genome. In the next two decades, numerous studies with progressively increasing levels of resolution made RBM the de facto theory of chromosome evolution. Despite the fact that RBM had prophetic prediction power, it was recently refuted by Pevzner and Tesler [4], who introduced the fragile breakage model (FBM), postulating that the human genome is a mosaic of solid regions (with low propensity for rearrangements) and fragile regions (rearrangement hotspots). However, the rebuttal of RBM caused a controversy and led to a split among researchers studying genome evolution. In particular, it remains unclear whether some complex rearrangements (e.g., transpositions) can create an appearance of rearrangement hotspots. We contribute to the ongoing debate by analyzing multi-break rearrangements that break a genome into multiple fragments and further glue them together in a new order. In particular, we demonstrate that (1) even if transpositions were a dominant force in mammalian evolution, the arguments in favor of FBM still stand, and (2) the ‘‘gene deletion’’ argument against FBM is flawed

Chromosomal breakpoint re-use in the inference of genome sequence rearrangement

In order to apply gene-order rearrangement algorithms to the comparison of genome sequences, Pevzner and Tesler [9] bypass gene finding and ortholog identification, and use the order of homologous blocks of unannotated sequence as input. The method excludes blocks shorter than a threshold length and ignores small block-internal rearrangements. Here we investigate possible biases introduced by eliminating and amalgamating short blocks, focusing on the notion of “breakpoint re-use ” introduced by these authors. Analytic and simulation methods show that re-use is very sensitive to threshold size and to parameters of the rearrangement process. As is pertinent to the comparison of mammalian genomes, large thresholds in the context of high rates of small rearrangements risk randomizing the comparison completely. We suggest a number of mathematical, algorithmic and statistical lines for further developing the Pevzner-Tesler approach