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. 2003 Jun 24;100(13):7672-7.
doi: 10.1073/pnas.1330369100. Epub 2003 Jun 16.

Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution

Pavel Pevzner  1 , Glenn Tesler
Affiliations

Human and mouse genomic sequences reveal extensive breakpoint reuse in mammalian evolution

Pavel Pevzner et al. Proc Natl Acad Sci U S A. .

Abstract

The human and mouse genomic sequences provide evidence for a larger number of rearrangements than previously thought and reveal extensive reuse of breakpoints from the same short fragile regions. Breakpoint clustering in regions implicated in cancer and infertility have been reported in previous studies; we report here on breakpoint clustering in chromosome evolution. This clustering reveals limitations of the widely accepted random breakage theory that has remained unchallenged since the mid-1980s. The genome rearrangement analysis of the human and mouse genomes implies the existence of a large number of very short "hidden" synteny blocks that were invisible in the comparative mapping data and ignored in the random breakage model. These blocks are defined by closely located breakpoints and are often hard to detect. Our results suggest a model of chromosome evolution that postulates that mammalian genomes are mosaics of fragile regions with high propensity for rearrangements and solid regions with low propensity for rearrangements.

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Figures

Fig. 1.
Fig. 1.
(Left) Histogram of synteny block lengths in human for Nb = 281 synteny blocks of length at least 1 Mb, fitted by an exponential distribution with mean block length L = GbNb = 9.6 Mb, where Gb = 2,707 Mb is the overall length of syntenic blocks. The bin size is 2.5 Mb. (Center) The same histogram superimposed with the 190 hidden synteny blocks revealed by genome rearrangement analysis, under the assumption that all hidden blocks are short, i.e., <1 Mb in length. (Right) Histogram of breakpoint region lengths in the human genome (bin size is 100 kb). Most breakpoint regions are very short, with 109 of 258 regions being <100 kb. However, there is a small number of long breakpoint regions: 17 regions are between 1 and 2.5 Mb, and 15 are <2.5 Mb (shown by a single bar at the right end). Chromosome ends can also host breakpoints, but are not included.
Fig. 2.
Fig. 2.
Two different most parsimonious scenarios that transform the order of the 11 synteny blocks on the mouse X chromosome into the order on the human X chromosome. The arrangement of synteny blocks in the ancestor is unspecified (and is assumed to coincide with one of intermediate arrangements) because it cannot be inferred without availability of a third genome (33, 41). Breakpoint uses are shown as short vertical yellow lines, and breakpoint region reuses are shown as double yellow lines. In the first scenario (Left) the breakpoint reuses are located in human in breakpoint regions (3,4), (4,5), and (5,6), whereas in the second one (Right) they are located in (5,6), (6,7), and after block 11. In the second scenario, a potential hidden block is shown as a black dot; it restricts the set of possible most parsimonious scenarios, and it separates two breakpoint uses that would have been a breakpoint region reuse. Our theory implies that any rearrangement scenario based on these 11 blocks has at least three reuses of breakpoint regions (possibly including chromosome ends).
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