Are There Rearrangement Hotspots in the Human Genome?

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Abstract
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. Rearrangements are genomic “earthquakes” that change the chromosomal architectures. The fundamental question in molecular evolution is whether there exist “chromosomal faults” (rearrangement hotspots) where rearrangements are happening over and over again. The random breakage model (RBM) postulates that rearrangements are “random,” and thus there are no rearrangement hotspots in mammalian genomes. RBM was proposed by Susumo Ohno in 1970 and later was formalized by Nadeau and Taylor in 1984. It was embraced by biologists from the very beginning due to its prophetic prediction power, and only in 2003 was refuted by Pevzner and Tesler, who suggested an alternative fragile breakage model (FBM) of chromosome evolution. However, the rebuttal of RBM caused a controversy, and in 2004, Sankoff and Trinh gave a rebuttal of the rebuttal of RBM. This led to a split among researchers studying chromosome evolution: while most recent studies support the existence of rearrangement hotspots, others feel that further analysis is needed to resolve the validity of RBM. In this paper, we develop a theory for analyzing complex rearrangements (including transpositions) and demonstrate that even if transpositions were a dominant evolutionary force, there are still rearrangement hotspots in mammalian genomes.