Hotspots of mammalian chromosomal evolution

Abstract

Background: Chromosomal evolution is thought to occur through a random process of breakage and rearrangement that leads to karyotype differences and disruption of gene order. With the availability of both the human and mouse genomic sequences, detailed analysis of the sequence properties underlying these breakpoints is now possible.

Results: We report an abundance of primate-specific segmental duplications at the breakpoints of syntenic blocks in the human genome. Using conservative criteria, we find that 25% (122/461) of all breakpoints contain > or = 10 kb of duplicated sequence. This association is highly significant (p < 0.0001) when compared to a simulated random-breakage model. The significance is robust under a variety of parameters, multiple sets of conserved synteny data, and for orthologous breakpoints between and within chromosomes. A comparison of mouse lineage-specific breakpoints since the divergence of rat and mouse showed a similar association with regions associated with segmental duplications in the primate genome.

Conclusion: These results indicate that segmental duplications are associated with syntenic rearrangements, even when pericentromeric and subtelomeric regions are excluded. However, segmental duplications are not necessarily the cause of the rearrangements. Rather, our analysis supports a nonrandom model of chromosomal evolution that implicates specific regions within the mammalian genome as having been predisposed to both recurrent small-scale duplication and large-scale evolutionary rearrangements.

Figure 1

Association of duplications and syntenic breaks: human versus mouse. (a) Top: ideogram of human chromosome 7 showing the positions of breakpoints in mouse-human synteny. We assessed only breakpoints that represented a change in orientation or difference in chromosome compared with the mouse genome (arrowheads). These breakpoints are designated as duplication-positive and duplication-negative (yellow and brown, respectively). Bottom: human chromosome 7 with blocks of conserved synteny with mouse indicated by colored bars. Segmental duplications are indicated by black bars over the sequence. Regions of duplication abutting the centromere and telomeres were excluded (gray shading). Small tick marks under the colored line represent 1-Mb intervals and breakpoints in synteny are numbered as in the chromosome ideogram. Gaps in conserved synteny were excluded. Conserved syntenic regions less than 100 kb or more than 75% duplicated were ignored. This prevented very small duplicated blocks from interrupting orthologous conservation or inappropriately increasing the number of breaks within a duplicated region. Breakpoints were scored as duplication-positive if they contained ≥ 10 kb of duplicated sequence. By these criteria, 13 of the 27 breakpoints on chromosome 7 (yellow boxes/arrows) were associated with duplications. (b) A histogram of the chromosomal distribution of syntenic breakpoints and their duplication status.

Figure 2

Simulation of random chromosomal breakage. We performed simulation studies to determine the significance of the observed association of segmental duplications with breakpoints by randomly reassigning breakpoints to positions within the assayed genomic sequence (see Materials and methods). Not once in 10,000 replicates did the simulated count exceed the observed number of duplication-positive breakpoints.