Genome rearrangements in mammalian evolution: lessons from human and mouse genomes

Abstract

Although analysis of genome rearrangements was pioneered by Dobzhansky and Sturtevant 65 years ago, we still know very little about the rearrangement events that produced the existing varieties of genomic architectures. The genomic sequences of human and mouse provide evidence for a larger number of rearrangements than previously thought and shed some light on previously unknown features of mammalian evolution. In particular, they reveal that a large number of microrearrangements is required to explain the differences in draft human and mouse sequences. Here we describe a new algorithm for constructing synteny blocks, study arrangements of synteny blocks in human and mouse, derive a most parsimonious human-mouse rearrangement scenario, and provide evidence that intrachromosomal rearrangements are more frequent than interchromosomal rearrangements. Our analysis is based on the human-mouse breakpoint graph, which reveals related breakpoints and allows one to find a most parsimonious scenario. Because these graphs provide important insights into rearrangement scenarios, we introduce a new visualization tool that allows one to view breakpoint graphs superimposed with genomic dot-plots.

Figure 1.

(a) Human and mouse synteny blocks. Every block corresponds to a rectangle, with a diagonal showing whether the arrangements of anchors in human and mouse (within the synteny block) are the same or reversed. (b) Combining anchors into clusters by the GRIMM-Synteny algorithm at G = 100 kb. The edges in the anchor graph connect the closest ends of the anchors. The anchors are color-coded by the resulting clusters. At G = 1 Mb, this forms a single cluster, which in turn forms a synteny block (the lower right block in the human 18/mouse 17 rectangle in a).

Figure 2.

X-chromosome: from local similarities, to synteny blocks, to breakpoint graph, to rearrangement scenario. (a) Dot-plot of anchors. Anchors are enlarged for visibility. (b) Clusters of anchors. (c) Rectified clusters. (d) Synteny blocks. (e) Synteny blocks (symbolic representation as genome rearrangement units). (f) 2D breakpoint graph superimposed on synteny blocks. The projections of the 2D graph onto the human and mouse axes form the conventional breakpoint graphs. (g) 2D breakpoint graph. The four cycles in the breakpoint graph are shown by different colors. (h) A most parsimonious rearrangement scenario for human and mouse X-chromosomes.

Figure 3.

Construction of the breakpoint graph from synteny blocks. (a) Solid path through human. (b) Dotted path through mouse. (c) Superposition of paths. (d) Remove blocks to obtain cycles.

Figure 4.

Multichromosomal breakpoint graph of the whole human and mouse genomes. The conventional chromosome order and orientation are not suitable for such graphs; an optimal chromosome order and orientation were determined by the algorithm in Tesler (2002b). Three “null chromosomes,” N1, N2, N3, were added to mouse to equalize the number of chromosomes in the two genomes.