This is a detailed description of the X chromosome scenario recovered in
G. Bourque, P. Pevzner, G. Tesler, Reconstructing the Genomic Architecture of Ancestral Mammals: Lessons from Human, Mouse, and Rat Genomes. Genome Research, in press, 2004.
This data is extracted from the GRIMM-Synteny analysis on human-mouse-rat at a 300 kb threshold (see html; the blocks here have been renumbered sequentially in human). At that threshold, there are 16 blocks common to human-mouse-rat and their order is
Human
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Mouse
-5 -6 4 13 14 -15 16 1 -3 9 -10 11 12 -7 8 -2
Rat
-13 -4 5 -6 -12 -8 -7 2 1 -3 9 10 11 14 -15 16
The order of blocks recovered in the putative ancestral X chromosome is
Ancestor
1 -3 9 10 11 12 5 2 -8 -7 -6 4 13 14 -15 16
The Multiple Genome Rearrangement Problem is to find a phylogenetic tree describing the most "plausible" rearrangement scenario for multiple species. MGR implements an algorithm which, given a set of genomes, seeks a tree such that the sum of the number of rearrangements (inversions, translocations, fissions, fusions) is minimized over all the edges of the tree. It can be used for phylogeny inference and also for inferrence of the ancestral gene orders. In the data below, we seek a maximum parsimony unrooted tree for the X chromosome under an inversions-only model for human, mouse, and rat.
(Rat:5,Mouse:5,Human:5)A3;
Score: 15 rearrangements
All ancestral nodes are coded by the letter A followed by a number
(e.g. A9).
+-------------------------------5---------------------------------Rat
|
| +-------------------------------5---------------------------------Mouse
+-A3
+-------------------------------5---------------------------------Human
The number of rearrangements that occured on each edge is shown. When no number is shown on an edge it means that no rearrangement occured on that edge. To view actual rearrangements events, click on an edge; it will describe one of the possible optimal sequence of rearrangements. It is also possible to click on the name of a node to view its gene sequence below.
| Human | Mouse | Rat | |
|---|---|---|---|
| Human | 0 | 10 | 10 |
| Mouse | 10 | 0 | 10 |
| Rat | 10 | 10 | 0 |
From the analysis above, we infer the rearrangement history of the mammalian X chromosome in human, mouse, and rat lineages. The arrangement of the 16 human-mouse-rat large-scale orthologous segments (each containing at least 300,000 nucleotides) located on the X chromosome is shown for the human, mouse, and rat genomes. Possible arrangements of the last common ancestor of mouse and rat (MR ancestor) were computed from these. The computations prove that the arrangement shown is the only one that minimizes the number of inversions of these segments on the paths to it from human, mouse, and rat. A possible order of those inversions is illustrated, but the actual order will not be determined until future studies allow more species to be added to this tree. Previous studies found that the arrangement of markers in the human X chromosome was unchanged since before the human-mouse-rat (HMR) ancestor, and our use of outgroup data from dog, cat, and cow is consistent with this (although we cannot rule out the possibility that the second segment from the right in human was inverted on the human lineage, see below).
The drawing of the creature at the ancestral node is probably similar to the placental ancestor. Artwork by G. Bourque, W. Murphy, P. Pevzner, and G. Tesler. Placental ancestor image used with permission from Nature 416, 816-822. Mouse photograph courtesy of Darryl Leja, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD. Rat photograph courtesy of Martin Krzywinski, Genome Sciences Centre, Vancouver, BC.
Tree 2:
Various data sets were used as outgroup data to identify the root of the above tree. As expected, the root of tree 2 was found to be on the ancestor-human edge of tree 1. This implies that the ancestor A3 that we recovered in tree 1 is the putative MR ancestor in tree 2. In order to infer the putative HMR ancestor, we used the same data sets to determine the position of the rearrangements on the ancestor-human edge of tree 1. From this analysis we concluded that the block arrangement of the HMR ancestor was identical to the block arrangement of human except potentially for block 15 (second from right in human) which may or may not have been inverted in the ancestor.
1. Human-mouse-cat-cowData described in
W.J. Murphy, G. Bourque, G. Tesler, P. Pevzner and S.J. O'Brien, Reconstructing the genomic architecture of mammalian ancestors using multispecies comparative maps. Human Genom. 1, 30–40 (2003).
Data obtained from a Radiation Hybrid map. Between human and cat on the X chromosome, there was complete agreement in the homologous marker order until near the end of the chromosome. This data was very low-resolution, and the markers did not have orientations, only approximate or relative positions. Thus, there could still be some flips of individual blocks that would go unnoticed. In any case, even with this event at the end of the X chromosome, the median still agrees with human and so all multiple block reversals must have occurred between the HMR and the MR ancestor. Similarly for comparing human and cow.
Data described in
E.F. Kirkness, et al. The dog genome: survey sequencing and comparative analysis. Science 301, 1898–1903 (2003).
We obtained a list of homologous human-dog markers from the TCAG group. The human coordinates were localized down to the nucleotide. The dog coordinates were just relative order. No orientation information was available due to the low coverage (1.5x). By using the human coordinates, we got an almost, but not quite, complete correspondence between the present human-mouse-rat blocks and their human-dog blocks, on the X chromosome.
The solution of the median problem using those blocks whose correspondence could be perfectly established, on input (human, dog, mouse-rat) with median at human-mouse-rat, was that the human and human-mouse-rat nodes were the same and the solution was unique. The catch is that this is just for the blocks whose correspondence could be perfectly established. There were some missing markers (but flanked by the same markers in both sets of blocks), and some missing orientation information. On taking that into account, there is a single block (2nd from right in human) that might have been flipped between the HMR ancestor and human, or between the HMR and the MR ancestor, while the other inversions were between the HMR and the MR ancestor.
The assignment of the accelerated activity to the rodent branch, following the primate-rodent divergence, is consistent with previous studies at significantly lower resolution, showing complete conservation of marker order between the X chromosomes of human and cat (Murphy, 1999) and human and lemur (Ventura, 2001), as well as similar karyotypes of the X chromosomes in human, chimpanzees, gorillas, and orangutans (Yunis, 1982) (the karyotypes have deletions in telomeres, but no rearrangements). Other studies showed only small rearrangements between the X chromosomes of human and pig (McCoard, 2002), and human and horse (Raudsepp, 2002). All of these species except the primates serve as evolutionary outgroups (Springer, 2003) to human, mouse, and rat, and all the primates (Thomas, 2003) have consistent order in the X chromosome, thus suggesting, independently of the current report, that the marker order on the human X chromosome is ancestral for the primate-rodent ancestor. Indeed, Lahn and Page (Lahn, 1999) showed evidence that the marker order on the human X chromosome has not changed since the ancestor 240-320 million years ago.
W.J. Murphy, S. Sun, Z.Q. Chen, J. Pecon-Slattery and S.J. O'Brien, Extensive conservation of sex chromosome organization between cat and human revealed by parallel radiation hybrid mapping. Genome Res. 9, 1223–1230 (1999).
M. Ventura, N. Archidiacono and M. Rocchi Centromere emergence in evolution. Genome Res. 11, 595–599 (2001).
J.J. Yunis and O. Prakash, The origin of man: a chromosomal pictorial legacy. Science 215, 1525–1530 (1982).
S.A. McCoard, S.C. Fahrenkrug, L.J. Alexander, B.A. Freking, G.A. Rohrer, T.H. Wise, J.J. Ford. An integrated comparative map of the porcine X chromosome. Anim Genet. 2002 Jun;33(3):178-85.
T. Raudsepp et al. Conservation of Gene Order between Horse and Human X Chromosomes as Evidenced through Radiation Hybrid Mapping Genomics, Volume 79, Issue 3, March 2002, Pages 451-457.
M.S. Springer, W.J. Murphy, E. Eizirik and S.J. O’Brien, Placental mammal diversification and the Cretaceous-Tertiary boundary. Proc. Natl Acad. Sci. USA 100, 1056–1061 (2003).
J.W. Thomas, et al. Comparative analyses of multi-species sequences from targeted genomic regions. Nature. 2003 Aug 14;424(6950):788-93.
B. Lahn and D.C. Page, Four evolutionary strata on the human X chromosome. Science, 1999 Oct 29;286(5441):964-7.