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Nucleic Acids Res. Dec 15, 2000; 28(24): 4974–4986.
PMCID: PMC115240

Comparison of the Escherichia coli K-12 genome with sampled genomes of a Klebsiella pneumoniae and three Salmonella enterica serovars, Typhimurium, Typhi and Paratyphi

Abstract

The Escherichia coli K-12 genome (ECO) was compared with the sampled genomes of the sibling species Salmonella enterica serovars Typhimurium, Typhi and Paratyphi A (collectively referred to as SAL) and the genome of the close outgroup Klebsiella pneumoniae (KPN). There are at least 160 locations where sequences of >400 bp are absent from ECO but present in the genomes of all three SAL and 394 locations where sequences are present in ECO but close homologs are absent in all SAL genomes. The 394 sequences in ECO that do not occur in SAL contain 1350 (30.6%) of the 4405 ECO genes. Of these, 1165 are missing from both SAL and KPN. Most of the 1165 genes are concentrated within 28 regions of 10–40 kb, which consist almost exclusively of such genes. Among these regions were six that included previously identified cryptic phage. A hypothetical ancestral state of genomic regions that differ between ECO and SAL can be inferred in some cases by reference to the genome structure in KPN and the more distant relative Yersinia pestis. However, many changes between ECO and SAL are concentrated in regions where all four genera have a different structure. The rate of gene insertion and deletion is sufficiently high in these regions that the ancestral state of the ECO/SAL lineage cannot be inferred from the present data. The sequencing of other closely related genomes, such as S.bongori or Citrobacter, may help in this regard.

INTRODUCTION

Escherichia coli K-12 has been the primary model in bacterial genetics for decades. While E.coli K-12 is not pathogenic, a number of other E.coli strains are pathogens and other closely related species are major pathogens of humans and animals (1, and references therein). Many of the differences between these organisms have been located on ‘pathogenicity islands’. The E.coli K-12 genome sequence has been completed (2) and a series of related pathogen genomes are in the process of being sequenced to completion or have been extensively sample sequenced by our group. Those that are publicly available are listed in Table Table11.

Table 1.
Divergence of the sampled genomes, relative to E.coli K-12

We have developed methods to visually portray DNA sequence information in a form that allows one completed genome, in this case E.coli K-12 (ECO), to be compared simultaneously with several sampled or completed genomes from related organisms (3). These tools are available for public use at http://globin.cse.psu.edu/ or via the Salmonella genome sequencing project at http://genome.wustl.edu/gsc/bacterial/newlistdisplay.pl.

Comparison of ECO with the other genomes allows the identification of all of the major differences between ECO and these organisms. We present a preliminary comparison of the E.coli K-12 genome with sample sequences of the genomes of Klebsiella pneumoniae (KPN) and the Salmonella enterica serovars Typhimurium, Typhi and Paratyphi A, collectively referred to as SAL. Genes that are present in ECO but absent in Salmonella or Klebsiella have been determined, clusters of ECO-specific genes have been located and the gross features of genetic reorganization have been examined.

MATERIALS AND METHODS

The E.coli K-12 sequence used is that reported by Blattner et al. (2). Sequence data for S.enterica serovars Typhimurium (STM) and Paratyphi A (SPA) and K.pneumoniae (KPN) were obtained from our sequencing project at ftp://genome.wustl.edu/pub/gsc1/sequence/st.louis/bacterial/Salmonella/, those for S.enterica serovar Typhi (STY) from ftp://ftp.sanger.ac.uk/pub/pathogens/st/ and Yersinia pestis (YPE) from ftp://ftp.sanger.ac.uk/pub/pathogens/yp/. Although they are not discussed further in this paper, the genomes for Vibrio cholerae (VCH) (www.tigr.org) and Pseudomonas aeruginosa (PAE) (www.pseudomonas.com) are also included in our comparative views. At the time of analysis two of the genomes, ECO and VCH, were complete, while the other genomes had been sequenced to varying extents. The numbers of melded contigs were: STM, 518; STY, 133; SPA, 887; YPE, 112; VCH, 2; PAE, 1.

Alignments of ECO with each of the other genomes were inspected with a web-based tool Enteric (3). For a user-supplied address in ECO the Enteric server scans pre-computed sets of pairwise alignments between ECO and each of the bacterial genomes and extracts those in the 20 kb region centered at the specified address. The alignments are computed by the program blastz (4). The Enteric server then produces a PDF document containing a hyperlinked, graphical representation of the selected alignments together with annotations that describe insertion, deletion and gene rearrangement events between the compared genomes. This consists of a set of percent identity plots (PIPs), as in Figure Figure11.

Figure 1
Enteric alignments of E.coli K-12 with six other genomes. PIP alignments of E.coli with genomes of six other bacteria, in the 20 kb region at the beginning of the E.coli sequence. See Materials and Methods and Florea et al. (3) for a description of how ...

In a PIP, a sequence match is shown as a line parallel to the horizontal axis at its relative position in the first (reference) sequence, positioned along the vertical axis at the coordinate corresponding to the percent identity of the match. Thus, a strongly conserved feature is represented as a horizontal line near the top of the PIP. Enteric produces a stacked array of PIPs, one for each of the comparisons between ECO and another bacterial genome, which show only alignments with 50–100% nucleotide identity.

Annotations of ECO genes are displayed above the PIPs, together with arrows indicating their orientations and with embedded hyperlinks to the corresponding entries in the WIT database (http://wit.IntegratedGenomics.com/IGwit/; 5). Other graphical features include colored rectangles or vertical bars, which denote discontinuities in the PIP alignments. When the cursor is placed over a particular region of the PIP, additional information is disclosed, such as the name of the aligning contig, the size of an inserted region or the ECO position of the adjacent gene in the other organism. More detailed instructions for how to read a PIP are presented in another paper (3). Users can generate their own PIPs using http://genome.wustl.edu/gsc/bacterial/newlistdisplay.pl or http://globin.cse.psu.edu/enterix/.

To measure the proportion of ECO genes present in each of the other genomes we proceed as follows. Each nucleotide in an ECO gene is assigned the highest percentage nucleotide identity found among all the alignments between ECO and the other genomes that include the nucleotide. This number is specified as 0% if no alignments contain that nucleotide. The average of these numbers over all nucleotides in an ECO gene provides a numerical value that assesses the strengths of those alignments for the whole gene. This value is adjusted where an unaligned ECO region is unsequenced in the other species. These gaps are identified as regions where the ends of sequenced contigs in the other species align with ECO (3). A 70% cut-off in this measurment of similarity was used to calculate the proportion of open reading frames (ORFs) shared between ECO and the other genomes in Table Table11.

The percent sequence similarity among putative orthologous ORFs was calculated by first identifying ECO ORFs that appeared to have homologs (defined as at least 50% similar) in the SAL, KPN and YPE genomes. Then known transposons and repetitive elements were excluded from this list. Among the 1388 ORFs that remained the percent similarity was determined for the 1000 with the highest overall similiarity to ECO in each genome. This measurement of similarity between the orthologous parts of ECO and the other genomes is given in Table Table11.

RESULTS AND DISCUSSION

The genomes will be referred to using the three letter abbreviations described in Table Table1.1. In addition, the abbreviation SAL will be used to indicate features in common among all three Salmonella genomes, STM, STY and SPA. Note that ECO refers to the E.coli K-12 MG1655 genome only and does not include other E.coli genomes.

Over 1000 genes in E.coli K-12 are absent from Salmonella and Klebsiella

The ECO and SAL genetic maps are generally co-linear and quite similar (6). However, evidence of substantial differences in their genomes has mounted (see for example 7). With the completion of the ECO genome and the near completion of some of its relatives, we can now quantify these differences.

The alignment of ECO with the SAL genomes contains many rearrangements or insertion/deletion events. To partially quantify these phenomena, genes that appear to have no close counterpart in the SAL lineage, when compared to ECO, were determined. Only genes that are absent in all three members of subspecies 1 of S.enterica (STM, STY and SPA) were considered. A threshold of 70% DNA sequence identity was used. This cut-off was chosen because these genomes share >80% DNA identity in their closest 1000 putative orthologs (Table (Table1).1). Thus, most orthologs should have sequence similarities of >70%. To minimize the chance that an unsequenced portion of a gene would result in an artificially low percent identity, the unsequenced portions of genes were excluded from the calculations (see Materials and Methods). The extent of completion of the sampled genomes (>95%) results in a <100 bp average gap size. If one assumes that particular sequences are not being excluded from the libraries, then, on average, fewer than one gene >500 bp in length would fail to be sampled per genome. However, there are many documented cases where genes are excluded from shotgun libraries. Thus, although it is extremely unlikely that a gene present in all three SAL would be unsampled by chance in all three genomes, it is possible that some genes have been missed due to selection against them in the libraries.

The list of 1350 genes (30.6%) that are present in ECO but lack a homolog with >70% sequence similarity in SAL is available at our web site (http://globin.cse.psu.edu/ftp/dist/Enterix/sim_pct.p70/missing_SAL.p70). The proportion of genes in ECO that appear not to have a close homolog in the three SAL is very similar to our previous estimate of 32%, which was made using a sample of only 7% of the sequence of STY (8). Others predicted 755 genes (18%) as most likely to have been acquired from distant foreign hosts (9). This discrepancy will require further analysis.

1165 ORFs were found in ECO but not in any SAL or in KPN   (http://globin.cse.psu.edu/ftp/dist/Enterix/sim_pct.p70/ missing_SAL_KPN.p70). KPN is a very close outgroup, only slightly more divergent from ECO than the three SAL genomes (see the number of shared genes and the DNA similarity of the best conserved ORFs in Table Table1).1). Only 138 (19%) of the 1165 ORFs have assigned gene names. In contrast, 2155 of 4405 genes (49%) are named in ECO. This difference may indicate that some of the genes found only in ECO have phenotypes in a narrow range of conditions that have not yet been found. For example, many genes in cryptic phage presumably contribute to fitness of ECO only indirectly, if at all. Table Table22 lists the subset of ORFs found in ECO, but absent or divergent in SAL or KPN, for which a function has been attributed. Their locations in the ECO genome and brief explanations of their known or putative biological role are also given. Genes with attributed functions that are absent or divergent in all three SAL but are present in KPN are listed in Table Table3.3. These tables are further annotated to show genes that have homologs with 50–70% DNA sequence identities. In some cases these genes with weaker homologies may be paralogs, but in other cases they probably represent genes that have experienced accelerated divergence or gene conversion events. Examples of the latter may include genes associated with proteins expressed on the surface (10), such as the flagella, pilin, fimbrial and lipopolysaccharide biosynthesis genes. These include the fli operon, flgA (2), ecpD (11), the rfa operon (1315), rfbCX (16) and the fim operon (12). There is a fim operon in at least some Salmonella sp. that is not orthologous to the ECO fim operon. However, the Salmonella operon does occur, unannotated, in the ECO genome (12; J.Parkhill, unpublished results). This observation highlights the fact that genes that are unannotated in the reference genome, in this case ECO, will automatically be missed using the strategy we employed here.

Table 2.
Escherichia coli K-12 genes with no close homologs in the K.pneumoniae and three Salmonella genomesa
Table 3.
Escherichia coli K-12 genes with close homologs in K.pneumoniae but absent in the three Salmonella genomesd

Among the genes and operons confirmed to be absent in SAL and KPN are those involved in glutamate metabolism (gadABC/xasAB) (17,18), glycolate utilization (glcCDFGB) (19), the glucuronide operon (uidRABC, gus) (2), the aga operon (20), the ato operon (21), the fec (ferric citrate transport) operon (22), the hca operon (23), the hde operon (24), emrE (a multidrug transporter) (25) and the entire dispersed family of ORFs of unknown function (rhsABCDE) (26,27). However, a set of distant family members does occur (J.Parkhill, unpubished results). The absence of certain other genes was less expected. OmpG is a cryptic phage gene in ECO that is expressed only after a mutation in the gene. Gene expression was reported at low levels in SAL (28), but we found that this gene and its close homologs are absent from SAL, indicating that the reported expression may be of a different gene.

Some genes are absent from only one SAL or KPN. These genes are not reported in Tables Tables22 and and33 but some are of particular interest, such as rffH, which is explored further elsewhere (3). It is likely that at least a few of the genes that are absent in our SAL and KPN genomes will prove to be present in the genomes of other strains of S.enterica or K.pneumoniae. Nevertheless, we can extrapolate from the very few genes that appear to be shared by ECO and only one out of three SAL (less than 30 such genes) that the lack of a homolog in our data analysis will usually mean lack of a homolog in virtually all the genomes in a species.

There are 394 events where one or more adjacent genes are absent in all three SAL relative to ECO (Table (Table4).4). 199 of these events involve more than one gene. Similarly, there were 216 cases where SPA has a sequence of >400 bases that is not found in ECO, 261 in STM and 257 in STY. There are at least 160 cases where the three SAL share sequences of >400 bases that are not found in ECO (Table (Table4).4). This number is in line with our previous estimate of a few hundred insertion/deletion events that distinguish these genomes, which was extrapolated from small samples of the genomes (8,29) and estimates based on the codon adaptation index (9).

Table 4.
Genome differences between E.coli K-12 and the three Salmonella spp.

If one discounts phage and transposable elements, both of which are probably not found in all ECO strains, and accepts that the SAL and ECO genomes diverged ~150 million years ago (30), then the rate at which ECO has acquired a sequence not found in SAL (through an insertion in ECO or deletion in SAL) approaches 2 per million years. On average, each event resulted in the insertion or deletion of about three ORFs. These are conservative estimates, as they do not take into account sequences gained and then lost during the past 150 million years.

Most of the genes unique to E.coli K-12 are in large clusters

It seemed likely that some of the 199 clusters of ECO-specific genes might be associated with known cryptic phage (see for example 31). These genes would presumably be absent from KPN as well as from the three SAL. The list of 1165 such genes (at a 70% DNA identity threshold) was examined for regions in which genes unique to ECO were separated by no more than 3 kb, to account for occasional close paralogs and recent insertions that might disrupt contiguous regions of sequence unique to ECO. This examination revealed 28 regions over 10 kb that consisted primarily of genes unique to ECO (Table 5). Four known cryptic lambdoid phage were identified within these largest clusters: Qin (within a 20 kb region), Rac (21 kb), e14 (27 kb) and DLP12/qsr′ (20 kb). A P4-like phage (32) may reside within a 32 kb cluster. Another cluster of 26 kb may include the CP4-6 prophage (33). The largest cluster, 46 kb, encodes genes with amino acid homology to Salmonella invasion genes and Vibrio toxR, though below the 70% DNA sequence similarity cut-off we have used to distinguish probable orthologs from other homologs. Many other very large clusters have no known association with phage. Perhaps some of these are plasmid integrations (34).

Table 5.
Escherichia coli K-12 gene clusters not found in the three Salmonella or the K.pneumoniae genomesa

Many differences involve insertion/deletion of single genes

Studies of the differences between E.coli and Salmonella have often focused on large groups of genes found in one species or the other (see for example 3537). However, even at a relaxed threshold of 50% sequence identity there are almost 100 sites where a single gene is absent in SAL but present in ECO and flanked by genes found in both genomes. None of these are known transposable elements nor do they have significant homologies to such elements. These observations add to the growing indications that it will not be sufficient to study a few large ‘pathogenicity islands’ in order to understand the myriad of genetic differences between Salmonella and E.coli. Deletions can also be associated with increased pathogenesis (38). It will be interesting to explore whether any of the 394 sequences that are missing in all three SAL have this effect.

Most of the genome is stable while the rest has sustained multiple changes

The ECO, KPN and SAL genomes are approximately equally divergent, with KPN appearing as a very close outgroup and Yersinia as a distant outgroup to these three genera, as indicated by the numbers of shared genes (Table (Table1)1) and the divergence from ECO exhibited by presumptive orthologs (84.5, 84.1, 84.2, 82.1 and 72.9% for STM, STY, SPA, KPN and YPE, respectively) (Table (Table1).1). Thus, it should be possible to predict the most parsimonious ancestral state when an ECO sequence is not present in at least one of the other lineages. This is important because the structure of the common ancestors of ECO and SAL and their common ancestor with KPN could help determine what functions were acquired on each lineage as it became specialized to its particular niche over a period that may be in excess of 150 million years (30). We inspected the PIPs for deletions shared by all three Salmonella genomes that were unchanged in the ECOKPN comparison. Such deletions would be suspected to have occurred in the SAL lineage. Sequences missing from both SAL and KPN would most likely indicate insertions in the ECO lineage. However, with the exception of some of the very large insertions attributable to prophage in ECO, there were relatively few simple insertion/deletion events that occurred in only one of the lineages. In many cases (20 of the first 50 we inspected) all three genomes appeared to have undergone insertions, deletions and rearrangements in the same or overlapping regions.

Two examples can be seen in Figure Figure1,1, located at 5 and 16 kb on the ECO genome. A simple absence of a gene occurs in the SAL genomes at 5 kb in the ECO genome, symbolized by the red box. [See Florea et al. (3) for details about PIPs.] However, the absence of this gene in KPN is accompanied by the insertion of an additional sequence of >400 bp (symbolized by the two blue stripes). An insertion also occurs at the same position in the distant outgroup YPE. However, analysis of the insertion in KPN and YPE shows that they are different from each other and not similar to any sequences yet found in any genome (not shown). Thus, there have been different events at this location in all of the genomes, making the ancestor impossible to determine without further comparisons with other related genomes, and perhaps not even then.

At 16 kb on the ECO map is another example where the SAL, KPN and ECO genomes all differ. The ECO sequence at this position includes a suspected insertion sequence and hence the ancestral state may be suspected to be absence of the genes. This hypothesis is supported by referral to the structure of YPE, a very distant enterobacteria, where this segment is missing. However, the SAL have a different sequence inserted at this site, leading to no prediction about the state of this region in the ECOSAL ancestor.

The ability to determine the ancestral state of the progenitor of these genera will presumably be aided by sample sequencing of other Enterobacteria, especially those other putative Escherichia and Salmonella, such as Escherichia blattae, Escherichia fergusonii, Escherichia hermannii, Escherichia vulneris and Salmonella bongori, as well as other closely related genera, particularly Citrobacter. However, it is likely that the state of the most recent common ancestor of ECO and SAL will remain unresolved at many positions even then.

It is biologically illuminating that so many insertion/deletion events cannot be explained by a single event. If these insertion/deletion events were randomly distributed over the genome one would expect two different insertions/deletions to occur only rarely in the same place in multiple lineages. The observation that the rearrangement events are concentrated in the same place in multiple lineages strongly implies that they are, at a minimum, excluded from large parts of the genome or perhaps in some cases targeted to a subset of the genome. It is these ‘hot-spots’ that appear to have sustained rearrangement events in separate lineages since the divergence of SAL, ECO and KPN.

In summary, an initial comparison of the ECO genome with the SAL and KPN genomes reveals the set of ECO genes that have no close homolog in SAL or KPN. Many genes found in ECO, but not in SAL or KPN, occur in very large clusters, some of which contain cryptic phage but some of which consist primarily of genes of unknown function. Nevertheless, a surprising number of differences involve single genes. Rearrangements appear to be concentrated in areas of the genome where the rate of rearrangement is rapid, relative to the divergence times of these organisms, so that many sites of rearrangement have sustained changes in more than one lineage. The data presented here comprise only the first of a number of possible genome comparisons. It will be interesting to use each of the other genomes in turn as the reference genome, in order to determine the sequences unique to each of the other lineages.

An additional feature of the data is that the genomes of K.pneumoniae (KPN) and S.enterica serovar Paratyphi A are samples with about 4× coverage and no immediate plans for completion. The data we were able to extract from these and the other incomplete genomes helps to demonstrate the utility of the relatively inexpensive sampled genome sequences for comparative genomics. However, one must bear in mind the caveats that some genes may be under-represented due to negative selection in the shotgun libraries and sequencing errors in samples means that one often cannot distinguish genes from pseudogenes. Nevertheless, with these caveats, the utility of sampled genomes, such as the KPN and SPA genomes that we have generated, and of the analysis of partial sequences of genomes undergoing completion, such as STM, STY and YPE, becomes increasingly evident as tools that can exploit these resources are developed.

ACKNOWLEDGEMENTS

We thank the members of the Salmonella sequencing consortium, in particular Monica Riley (Woods Hole), Michael Nhan and John Spieth (WUSTL), and Aaron McKay and Bill Pearson (University of Virginia) for their cooperation and many helpful discussions. We particularly thank the members of the Sanger sequencing efforts on S.typhi and Y.pestis for giving us permission to use their data prior to publication. We thank Steffen Porwollik, David Boyle and John Welsh for critical reading of the manuscript. This work was supported by grants AI 34829-09 AI (R.K.W.), AI 34829 (M.M.) and LM05110 (W.M.). Sequencing of S.typhi and Y.pestis at The Sanger Centre was funded by the Wellcome Trust through its Beowulf Genomics initiative.

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