Evidence for symmetric chromosomal inversions around the replication origin in bacteria
© GenomeBiology.com 2000
Received: 7 August 2000
Accepted: 19 October 2000
Published: 4 December 2000
Whole-genome comparisons can provide great insight into many aspects of biology. Until recently, however, comparisons were mainly possible only between distantly related species. Complete genome sequences are now becoming available from multiple sets of closely related strains or species.
By comparing the recently completed genome sequences of Vibrio cholerae,Streptococcus pneumoniae and Mycobacterium tuberculosis to those of closely related species - Escherichia coli, Streptococcus pyogenes and Mycobacterium leprae, respectively - we have identified an unusual and previously unobserved feature of bacterial genome structure. Scatterplots of the conserved sequences (both DNA and protein) between each pair of species produce a distinct X-shaped pattern, which we call an X-alignment. The key feature of these alignments is that they have symmetry around the replication origin and terminus; that is, the distance of a particular conserved feature (DNA or protein) from the replication origin (or terminus) is conserved between closely related pairs of species. Statistically significant X-alignments are also found within some genomes, indicating that there is symmetry about the replication origin for paralogous features as well.
The most likely mechanism of generation of X-alignments involves large chromosomal inversions that reverse the genomic sequence symmetrically around the origin of replication. The finding of these X-alignments between many pairs of species suggests that chromosomal inversions around the origin are a common feature of bacterial genome evolution.
Large-scale genomic rearrangements and duplications are important in the evolution of species. Previously, these large-scale genome-changing events were studied through genetic or cytological studies. With the availability of many complete genome sequences it is now possible to study such events through comparative genomics. The publication of the yeast genome has led to much better insight into the duplication events that have occurred in fungal and eukaryotic evolution (for example, see ). Large chromosomal duplications have also been found from analysis of completed chromosomes of Arabidopsis thaliana [2,3]. The ability to detect large-scale genomic changes is dependent in large part on which genomes are available. Such studies in bacteria, for example, have been limited by the availability of genomes only from distantly related sets of species. Recently, however, the genomes of sets of closely related bacterial species have become available. We have compared these closely related bacterial genomes and have discovered an unusual phenomenon - alignments of whole genomes that show an X-shaped pattern (which we refer to as X-alignments). Here we present the evidence for these X-alignments and discuss mechanisms that might have produced them.
Results and discussion
Whole-genome X-alignments between species at the DNA level
Whole-genome DNA alignments using MUMmer
4.7 ± 10-59
V. cholerae (rev)
1.8 ± 10-90
V. cholerae (rev)
8.2 ± 10-16
E. coli (rev)
1.5 ± 10-23
4.5 ± 10-80
S. pyogenes (rev)
2.3 ± 10-90
S. pyogenes (rev)
1.1 ± 10-18
S. pneumoniae (rev)
1.5 ± 10-6
M. leprae (rev)
3.5 ± 10-10
M. tuberculosis (rev)
E. coli (rev)
We have found that X-alignments of whole genomes are not limited to the V. cholerae versus E. coli comparison. For example, a whole-genome comparison of two bacteria in the genus Streptococcus - S. pyogenes  and S. pneumoniae (H. Tettelin, personal communication) - reveals a global X-alignment similar to that of V. cholerae versus E. coli (Figure 1d) which is also statistically significant (Table 1). In addition, an X-alignment is found between two species in the genus Mycobacterium - M. tuberculosis  and M. leprae  (Figure 1e) - as well as between two strains of Helicobacter pylori (data not shown). The X-alignments observed between any two pairs of genomes are not identical in every aspect. For example, in the alignment between the two Mycobacterium species, each conserved region is much longer than in the other genome pairs. We believe this is due to different numbers of evolutionary events between the species (see below). Whole-genome X-alignments were not found between any other pairs of species, although a related pattern was seen between some of the chlamydial species (see below).
Whole-genome X-alignments between species are also found at the proteome level
Whole-genome protein-level comparisons
3.2 ± 10-40
V. cholerae (rev)
2.3 ± 10-70
3.6 ± 10-17
V. cholerae (rev)
3.6 ± 10-10
E. coli (rev)
1.0 ± 10-15
V. cholerae (rev)
8.4 ± 10-4
Whole-genome X-alignments within species
Model I: whole-genome inverted duplications
One possible explanation for an X-alignment within and between species is an ancestral inverted duplication of the whole genome, as has been suggested for E. coli . The weak or missing X-alignment within species could be explained by gene loss of one of the two duplicates of many of the pairs of genes in the different lineages. Gene loss has been found to follow large chromosomal or genome duplications [11,12,13]. This gene loss is thought to stabilize large duplications by preventing recombination events between duplicate genes. If gene loss is responsible for the weak X-alignment within species, then to maintain the X-alignments between species, the member of the gene pair lost in a particular lineage should be essentially random. If an ancient inverted duplication followed by differential gene loss is the correct explanation for the observed X-alignments, one would expect the genes along one diagonal to be orthologous between species (related to each other by the speciation event), while the genes along the other diagonal should be paralogous (related to each other by the genome duplication event before the speciation of the two lineages). However, the evidence appears to contradict this model: likely orthologous gene pairs are equally distributed on each diagonal (data not shown).
Model II: chromosomal inversions about the origin and/or terminus
Inversions about the origin and terminus could also produce an X-alignment within species, through the splitting of tandemly duplicated sequence. Many sets of tandemly duplicated genes are found in most bacterial genomes [19,20] (also see Figure 3a,c). As tandem duplications are inherently unstable (one of the duplicates can be rapidly eliminated by slippage and/or recombination events ), the fact that many tandem pairs are present within each genome suggests that tandem duplications occur frequently. Thus, it is reasonable to assume that occasionally a large inversion will split a pair of tandemly duplicated genes. An inversion that pivots about the origin and also splits a tandem duplication will result in a pair of paralogous genes spaced symmetrically on opposite sides of the origin.
If our inversion model is correct, then the genes along both diagonals in the between-species alignments should be orthologous, which is the case (see above). In contrast, genes along the anti-diagonal in the within-species X-alignments should be recent tandem duplicates that have been separated by inversions. This also appears to be the case - in the within-species analysis of V. cholerae chrI ORFs, the X-alignment shows up best when only recent duplicates are analyzed (Figure 2d). The splitting of tandem duplicates by inversions may be a general mechanism to stabilize the coexistence of duplicated genes, as it will prevent their elimination by unequal crossing-over or replication slippage events.
What could cause inversions that pivot around the origin and terminus of the genome to occur more frequently than other inversions? One possibility is that many inversions occur, but there is selection against those that change the distance of a gene from the origin or terminus. Such a possibility has been suggested by experimental work in E. coli [14,15]. Additional studies have, however, suggested that there is little selective difference between inversions and that instead there may be certain regions that are more prone to inversion than others [16,17,18,22,23]. Alternatively, the inversion events could be linked to replication, as has been suggested for small local inversion events . Whatever the mechanisms, the fact that we find evidence for such inversions between many pairs of species suggests that they are a common feature of bacterial evolution. Many aspects of the X-alignments require further exploration. For example, to split a tandem duplication, an inversion must fall precisely on the boundary between two duplicated genes. This would appear to be unlikely, requiring a large number of inversions in order to generate a sufficient number of split gene pairs. If the mechanisms of gene duplication are somehow related to the mechanisms of inversion, however, then this model is more plausible. The process of duplicating a gene, if it occurs during replication, might promote a recombination event within the bacterial chromosome that inverts the sequence from the origin up to that point. As with inversion events, recombination and replication have been found to be tightly coupled .
We present here a novel observation regarding the conservation between bacterial species of the distance of particular genes from the replication origin or terminus. The initial observation was only possible due to the availability of complete genome sequences from pairs of moderately closely related species (for example, V. cholerae and E. coli). This shows the importance of having genome pairs from many levels of evolutionary relatedness. Comparisons of distantly related species enable the determination of universal features of life as well as of events that occur very rarely. Comparison of very closely related species allows the identification of frequent events such as transitional changes at third codon positions or tandem duplications. To elucidate all other events in the history of life, genome pairs covering all the intermediate levels of evolutionary relatedness will be needed.
Materials and methods
Complete published genome sequences were obtained from the National Center for Biotechnology Information website  or from the TIGR Comprehensive Microbial Resource . These included Aeropyrum pernix , Aquifex aeolicus , Archaeoglobus fulgidus , Bacillus subtilis , Borrelia burgdorferi , Campylobacter jejuni , Chlamydia pneumoniae AR39 , Chlamydia pneumoniae CWL029 , Chlamydia trachomatis (D/UW-3/Cx) , Chlamydia trachomatis MoPn , Deinococcus radiodurans , Escherichia coli , Haemophilus influenzae , Helicobacter pylori , Helicobacter pylori J99 , Methanobacterium thermoautotrophicum , Methanococcus jannaschii , Mycobacterium tuberculosis , Mycoplasma genitalium , Mycoplasma pneumoniae , Neisseria meningitidis MC58 , Neisseria meningitidis serogroup A strain Z2491 , Pyrococcus horikoshii , Rickettsia prowazekii , Synechocystis sp. , Thermotoga maritima , Treponema pallidum , and Vibrio cholerae . In addition, a few unpublished genomes were analyzed: Streptococcus pyogenes (obtained from the Oklahoma University Genome Center website ), Streptococcus pneumoniae (H. Tettelin, personal communication), and Mycobacterium leprae (obtained from the Sanger Centre Pathogen Sequencing Group website ).
Whole-genome DNA alignments
DNA alignments of the complete genomic sequences of all bacteria used in this study were accomplished with the MUMmer program . This program uses an efficient suffix tree construction algorithm to rapidly compute alignments of entire genomes. The algorithm identifies all exact matches of nucleotide subsequences that are contained in both input sequences; these exact matches must be longer than a specified minimum length, which was set to 20 base pairs for this comparison. To search for genome-scale alignments within species, complete bacterial and archaeal genomes (25 in total including all published genomes) were aligned with their own reverse complements. To search for between-species alignments, all genomes were aligned against all others in both orientations.
Whole-genome protein comparisons
The predicted proteome of each complete genome sequence (all predicted proteins in the genome) was compared to the proteomes of all complete genome sequences (including itself) using the fasta3 program . Matches with an expected score (e-value) of 10-5 or less were considered significant.
Statistical significance of X-alignments
To calculate the statistical significance of the X-alignments, the maximal unique matching subsequences (MUMs) for unrelated genomes were examined and found to be uniformly distributed . With a uniform background, the expected density of MUMs in any region of an alignment plot is a simple proportion of the area of that region to the entire plot. In particular, in an alignment with N total MUMs, the probability (Pr) of observing at least m matches in a region with area p can be computed using the binomial distribution in Equation 1:
The alignment of V. cholerae chrI (both forward and reverse strands) versus E. coli contains 926 MUMs. The MUMs forming X-alignments appear along the diagonal (y = x) and the anti-diagonal (y = L -x, where L is the genome length). To estimate the significance of the alignments in both directions, diagonal strips were sampled along each of the diagonals. The width of each strip was set at 10% of the plot area and significance values were calculated (Table 1).
Identification of origins of replication
The origins of replication for the bacterial genomes have been characterized by a variety of methods. For E. coli, M. tuberculosis and M. leprae, the origins have been well-characterized by laboratory studies [51,52]. The origins and termini of C. trachomatis, C. pneumoniae and V. cholerae were identified by GC-skew  and by characteristic genes in the region of the origin [4,19]. GC-skew uses the function (G-C)/(G+C) computed on 2,000 bp windows across the genome, which exhibits a clear tendency in many bacterial genomes to be positive for the leading strand and negative for the lagging strand. The origin of H. pylori was determined by oligomer skew  and confirmed by GC-skew. The origins and termini of S. pneumoniae and S. pyogenes were determined by the authors of the present study using GC-skew analysis and the locations of characteristic genes, particularly the chromosome replication initiator gene dnaA.
We thank S. Eddy, M.A. Riley, T. Read, A. Stoltzfus, M-I Benito and I. Paulsen for helpful comments, suggestions and discussions. S.L.S. was supported in part by NSF grant IIS-9902923 and NIH grant R01 LM06845. S.L.S. and J.A.E were supported in part by NSF grant KDI-9980088. Data for all published complete genome sequences were obtained from the NCBI genomes database  or from The Institute for Genomic Research (TIGR) Microbial Genome Database . The sequences of V. cholerae, S. pneumoniae, and M. tuberculosis (CDC 1551) were determined at TIGR with support from NIH and the NIAID. The M. leprae sequence data were produced by the Pathogen Sequencing Group at the Sanger Centre. Sequencing of M. leprae is funded by the Heiser Program for Research in Leprosy and Tuberculosis of The New York Community Trust and by L'Association Raoul Follereau. The M. tuberculosis CDC 1551 genome sequence was obtained from TIGR. The source of the S. pyogenes genome sequence was the Streptococcal Genome Sequencing Project funded by USPHS/NIH grant AI38406, and was kindly made available by B. A. Roe, S.P. Linn, L. Song, X. Yuan, S. Clifton, R.E. McLaughlin, M. McShan and J. Ferretti, and can be obtained from the website of the Oklahoma University Genome Center .
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