Are There Rearrangement Hotspots in the Human Genome?

Max Alekseyev,Pavel A Pevzner

doi:10.1371/journal.pcbi.0030209.eor

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.

Highlights

In 1970, Susumu Ohno came up with two fundamental models of chromosome evolution that were subject to many controversies in the last 35 years [1]
The other, the random breakage model (RBM), had a very different fate. It was embraced by biologists from the very beginning and only recently was refuted by Pevzner and Tesler [4] using a theorem from [5]
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

Summary

Introduction

In 1970, Susumu Ohno came up with two fundamental models of chromosome evolution that were subject to many controversies in the last 35 years [1]. The other, the random breakage model (RBM), had a very different fate. It was embraced by biologists from the very beginning (due to its prophetic prediction power) and only recently was refuted by Pevzner and Tesler [4] using a theorem from [5]. 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. RBM postulates that rearrangements are ‘‘random,’’ and there are no rearrangement hotspots in mammalian genomes

Methods

Results

Discussion

Conclusion