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Comparative Study
. 2004 Apr;14(4):507-16.
doi: 10.1101/gr.1975204.

Reconstructing the genomic architecture of ancestral mammals: lessons from human, mouse, and rat genomes

Guillaume Bourque  1 , Pavel A Pevzner, Glenn Tesler
Affiliations
Comparative Study

Reconstructing the genomic architecture of ancestral mammals: lessons from human, mouse, and rat genomes

Guillaume Bourque et al. Genome Res. 2004 Apr.

Abstract

Recent analysis of genome rearrangements in human and mouse genomes revealed evidence for more rearrangements than thought previously and shed light on previously unknown features of mammalian evolution, like breakpoint reuse and numerous microrearrangements. However, two-way analysis cannot reveal the genomic architecture of ancestral mammals or assign rearrangement events to different lineages. Thus, the "original synteny" problem introduced by Nadeau and Sankoff previously, remains unsolved, as at least three mammalian genomes are required to derive the ancestral mammalian karyotype. We show that availability of the rat genome allows one to reconstruct a putative genomic architecture of the ancestral murid rodent genome. This reconstruction suggests that this ancestral genome retained many previously postulated chromosome associations in the placental ancestor and reveals others that were beyond the resolution of cytogenetic, radiation hybrid mapping, and chromosome painting techniques. Three-way analysis of rearrangements leads to a reliable reconstruction of the genomic architecture of specific regions in the murid ancestor, including the X chromosome, and for the first time allows one to assign major rearrangement events to one of human, mouse, and rat lineages. Our analysis implies that the rate of rearrangements is much higher in murid rodents than in the human lineage and confirms the existence of rearrangement hot-spots in all three lineages.

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Figures

Figure 1
Figure 1
(A) The 162 two-way synteny blocks between mouse and rat, of size at least 300 kb, computed by direct two-way comparison of mouse and rat. Synteny blocks are shown as rectangles with a diagonal stripe to indicate direction. (B) The 391 three-way human–mouse–rat syntenic blocks of size at least 300 kb, shown in their mouse–rat coordinates. Introducing human splits of many of the synteny blocks in A into smaller ones in B, and also removes regions that do not have a human homolog. Higher quality versions of these plots are available in the Supplemental materials.
Figure 3
Figure 3
Ancestral murid rodent genome (A) and evolutionary tree computed by MGR, using mouse and rat with human as an outgroup. Each genome is represented as an arrangement of 391 synteny blocks (longer than 300 kb) as computed by GRIMM-Synteny. The synteny blocks are each represented as one unit, regardless of their length in nucleotides. Chromosomes with too many blocks are split into two lines. Each human chromosome is assigned a unique color, and a diagonal line is drawn through the whole chromosome. In other genomes, this diagonal line indicates the relative order and orientation of the rearranged blocks. The phylogram at the top of the figure indicates the number of rearrangements required to convert each genome (human, mouse, rat) into A, as computed by MGR. The estimated dates of divergence are from Springer et al. (2003).
Figure 2
Figure 2
Region on human chromosome 17, mouse chromosome 11, rat chromosome 10. (A) Local two-way similarities produced by PatternHunter (darker ones are longer; some short mouse–rat ones were removed for legibility). Synteny blocks appear as ±45° diagonals. Repeats tend to appear as discrete grids with irregular spacing. (B) After removing repeated regions and combining close alignments, GRIMM-Synteny computes 19 large-scale synteny blocks (at least 300 kb). The same synteny blocks are shown in each pair of species, using consistent colors. (C) The arrangement (order and orientation) of the 19 synteny blocks in this region is shown for each genome. MGR determined that there is a unique median ancestor associated with the most parsimonious evolutionary scenarios of the three genomes in this region; note that it coincides with mouse. The arrangement of blocks in this region implies there were at least 12 inversions between human and the median, and at least two inversions between rat and the median. The chronological order of the inversions cannot be inferred from this method. Note also that the minimum number of inversions required to convert the human block order in this region into the rat order is 14, so the solution shown is optimal, and all optimal solutions have equal block arrangements on median and mouse.
Figure 4
Figure 4
Histograms of lengths of two-way synteny blocks for each pair of species, fitted by the exponential distribution predicted by the statistical model in Nadeau and Taylor (1984). The mouse–rat block lengths appear to deviate from this model.
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