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. 2004 Oct;14(10A):1851-60.
doi: 10.1101/gr.2663304. Epub 2004 Sep 13.

Human, mouse, and rat genome large-scale rearrangements: stability versus speciation

Shaying Zhao  1 , Jyoti Shetty, Lihua Hou, Arthur Delcher, Baoli Zhu, Kazutoyo Osoegawa, Pieter de Jong, William C Nierman, Robert L Strausberg, Claire M Fraser
Affiliations

Human, mouse, and rat genome large-scale rearrangements: stability versus speciation

Shaying Zhao et al. Genome Res. 2004 Oct.

Abstract

Using paired-end sequences from bacterial artificial chromosomes, we have constructed high-resolution synteny and rearrangement breakpoint maps among human, mouse, and rat genomes. Among the >300 syntenic blocks identified are segments of over 40 Mb without any detected interspecies rearrangements, as well as regions with frequently broken synteny and extensive rearrangements. As closely related species, mouse and rat share the majority of the breakpoints and often have the same types of rearrangements when compared with the human genome. However, the breakpoints not shared between them indicate that mouse rearrangements are more often interchromosomal, whereas intrachromosomal rearrangements are more prominent in rat. Centromeres may have played a significant role in reorganizing a number of chromosomes in all three species. The comparison of the three species indicates that genome rearrangements follow a path that accommodates a delicate balance between maintaining a basic structure underlying all mammalian species and permitting variations that are necessary for speciation.

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Figures

Figure 1
Figure 1
Syntenic block length distribution. The numbers of blocks with length above 100 kb in 2.5-Mb bins are plotted in blue. Expected values at 95% confidence for each bin on the basis of the Monte Carlo simulation of the random breakage model are plotted in pink. The data indicate that there are significantly more small blocks than what are predicated by the random breakage model, further confirmed by examining the distributions of the sum of sizes of the largest 40 blocks (as shown in the insets, the predicated values are smaller). (Top) The synteny between mouse and rat. (Bottom) The synteny among mouse, rat, and human. (Insets) Distributions of the sum of the lengths (kb) of the largest 40 blocks for the observed data (blue) and the predicated values at 95% confidence based on the random model (pink).
Figure 2
Figure 2
The mouse/rat synteny. Each block represents a mouse (blue) or rat (pink) chromosome (e.g., M1, mouse chromosome 1; R1, rat chromosome 1). A line was drawn between a mouse block and a rat block if synteny was found between the two chromosomes. This plot better reveals the interactions between the chromosomes within a genome compared with other synteny plots used (Waterston et al. 2002; Kirkness et al. 2003; Rat Sequencing Project Consortium 2004) as demonstrated by the following. (1) Except for the M9/R8 and X chromosomes, the rest of the chromosomes have exchanged genetic materials with other chromosomes forming a complex synteny network. (2) Within the network, chromosomes also display varying degrees of complexity in synteny. For instance, mouse chromosomes M3, M4, M6, M7, M12, and M19 are syntenic only to a single rat chromosome. The same is true for R3, R11, R15, R18, and R19. The remaining chromosomes are syntenic to 2 to 3 chromosomes from the other species, except for R1, M5, and M17 with synteny to 5, 4, and 7 chromosomes, respectively. (3) M17 has the most complex synteny. Compared with its rat homologs, M17 has additionally rearranged with M10 and M1 multiple times, as well as with M5, M11, and M16 at least once. Nearly every mouse/rat syntenic block in M10 and M1 has rearranged with M17, indicating subsequent fusions of these blocks forming the two chromosomes. (4) Chromosomes within the network seem to group together on the basis of the conservation and rearrangement between the two species. For instance, chromosomes located at the left (M8/M14 vs. R19/R16/R15), where rat is more rearranged, differ from those at the bottom, right corner (M17/M1/M4 vs. R9/R13/R5), where mouse is more rearranged. Similarly, whereas a large variation was found between M17/M10/M7/M19 and R7/R20/R1 at the right, a great conservation was identified between M3/M13/M15/M2/M18 and R2/R17/R3/R18/R7 at the top.
Figure 3
Figure 3
Intrachromosomal rearrangements in H7. H7p's first 32 Mb and the entire H7q are syntenic to R4(1-86 Mb)/M5(27-3)/M6(3-57), R12(9.7-27)/M5(143-128), R6(49-64)/M12(25-39)a, and R6(143-148)/M12(110-115)b (numbers in parentheses are in megabases). However, each of these continuous mouse/rat fragments broke and formed multiple syntenic blocks that scatter on both arms of H7. Blocks belonging to the same mouse/rat fragment are in the same color and numerically numbered on the basis of their orders in the fragment. For example, fragment R12/M5 split into four blocks with the second (labeled as “R12/M5, 2” in the plot) syntenic to the beginning of H7p and the other three to H7q. These portions of H7 are possibly derived from the large ancestral fragment H7a (blocks with solid lines). The rest of H7p, syntenic to R8(22-25Mb)/M9(22-25), R17(51.6-58)/M13(20-15), and R14(87-99)/M11(6.3-17), are possibly from the small ancestral fragment H7b (blocks with dashed lines). Block sizes are somewhat arbitrary and do not reflect the actual fragment length. Using dog as outgroup, among a total of 20 breakpoints shown, seven are due to human-specific intrachromosomal rearrangements (red lines on the right), eight are mouse/rat specific (blue lines), and five are shared by mouse/rat/dog (black lines, solid lines indicating where mouse/rat and dog break at the same site, dashed lines indicating where mouse/rat and dog break at slightly different [within 1-2 Mb] sites).
Figure 4
Figure 4
A possible evolution path of H20, based on its synteny to M2/R3. The last 50-60-Mb fragment was broken off an ancestral chromosome that evolved to M2/R3. The fragment further split into three pieces with an approximate size of 24, 1.5, and 34 Mb, respectively. Then, the middle 1.5-Mb piece was moved to the tip, inverted, and fused with the 24-Mb piece, forming the p-arm, whereas the 34-Mb piece formed the q-arm. A centromere formed between the two arms where the original middle 1.5 Mb was located.
Figure 5
Figure 5
An apparent differential use of the two arms of HX in mouse and rat. Through several breakages and inversions, HX can be transformed to five fragments of MX as well as five fragments of RX (numerically numbered in blocks as MX1, MX2, or RX1, RX2...). Specifically, HXp corresponds to three fragments of MX (the last 20 Mb, a middle 17 Mb, and the start 16 Mb), and to two middle fragments of RX. HXq corresponds to three fragments of RX (the last 78 Mb, a middle 9 Mb, and the start 12 Mb), and to two middle fragments of MX. Blocks with the same fragment number in both mouse and rat are indicated with the same color (e.g., MX1 and RX1 are both represented as white blocks). Block sizes are somewhat arbitrary and do not reflect the actual fragment length. MX1: 3-19 Mb, MX2: 19.3-61, MX3: 80-63, MX4: 80-130, MX5a: 133-130, and MX5b: 150-135. RX1: 12-0.8, RX2: 29-12, RX3: 38-29, RX4a: 42-40, RX4b: 44-82, RX5a: 82-129, and RX5b: 132-160 (fragment ranges are all in Mb).
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WEB SITE REFERENCES

    1. ftp://ftp.tigr.org/pub/data/Bac_Resource/HumanMouseRatSynteny; mouse/rat/human synteny data used in this study.
    1. http://bacpac.chori.org; providing BAC clones.
    1. http://ftp.genome.washington.edu/RM/RepeatMasker.html; providing the RepeatMasker program.
    1. http://sapiens.wustl.edu/blast/; providing the WUBLAST program.
    1. www.ensembl.org; providing genomic sequence resource for various species.

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