Gene socialization: gene order, GC content and gene silencing in Salmonella
© Papanikolaou et al; licensee BioMed Central Ltd. 2009
Received: 10 June 2009
Accepted: 11 December 2009
Published: 11 December 2009
Genes of conserved order in bacterial genomes tend to evolve slower than genes whose order is not conserved. In addition, genes with a GC content lower than the GC content of the resident genome are known to be selectively silenced by the histone-like nucleoid structuring protein (H-NS) in Salmonella.
In this study, we use a comparative genomics approach to demonstrate that in Salmonella, genes whose order is not conserved (or genes without homologs) in closely related bacteria possess a significantly lower average GC content in comparison to genes that preserve their relative position in the genome. Moreover, these genes are more frequently targeted by H-NS than genes that have conserved their genomic neighborhood. We also observed that duplicated genes that do not preserve their genomic neighborhood are, on average, under less selective pressure.
We establish a strong association between gene order, GC content and gene silencing in a model bacterial species. This analysis suggests that genes that are not under strong selective pressure (evolve faster than others) in Salmonella tend to accumulate more AT-rich mutations and are eventually silenced by H-NS. Our findings may establish new approaches for a better understanding of bacterial genome evolution and function, using information from functional and comparative genomics.
The conservation of gene order has been found to play an essential role in genome evolution. More specifically, proteins encoded by genes of conserved order in bacteria tend to evolve more slowly when compared to proteins encoded by genes without a conserved order [1, 2] and genes with similar or related functions tend to occur in adjacent chromosomal positions in yeast . Moreover, genes with conserved order were found to evolve at similar rates  and, in prokaryotes, proteins encoded by genes with conserved order appear to interact physically . It has also been shown that in eukaryotes essential genes are clustered in regions with low recombination rates , whereas in bacteria essential genes are more conserved than non essential genes . In addition, it has been reported that the number of interactions involved in a protein network is directly correlated with the rate of evolution among these proteins  and that highly expressed genes evolve slowly [8, 9]. A case in point for the role of gene order in evolution can be illustrated by duplicated genes . Following a duplication event one of the two (paralog) genes might keep its original function, whereas the other one might be under less selective pressure. Yet, it is not always readily apparent which duplicated genes evolve faster. There have been reports that have marginally correlated sequence conservation with genome context , but there must be other, yet unknown, functional features that determine the fate of duplicate genes.
Recently, two research groups observed independently that the histone-like nucleoid structuring protein (H-NS) plays an important role as a general transcriptional repressor of a large number of genes in Salmonella enterica serovar Typhimurium LT2 (S. Typhimurium) [12, 13]. H-NS is a protein that is believed to play an essential role in the organization and compaction of bacterial chromatin as well as in transcriptional regulation for many bacterial genes [14–16]. H-NS binds to these genes and silences them transcriptionally. An apparent common feature of genes silenced by H-NS is that their GC content is significantly lower than the overall GC content of the Salmonella genome . Additionally, a large proportion of these H-NS repressed genes is predicted to have been acquired from a foreign source (horizontally transferred genes, HTGs) [13, 15], a fact in agreement with the observation that HTGs are relatively AT-rich [17, 18]. It has been suggested that this may be a defensive mechanism against foreign genetic material without loosing the benefit of future usage of this material if necessary .
Herein, we aimed to test the correlation between gene order conservation, gene duplication and H-NS dependent silencing in S. Typhimurium, using Escherichia coli K12 as a reference genome in order to identify the conservation or loss of gene order along the bacterial chromosome. We have also attempted to associate the above mentioned features with GC content and gene essentiality.
Evolutionary rate and GC content are related to genomic neighborhood conservation
In order to check the former hypothesis, we cross-checked the three groups for the existence of HTGs in the Salmonella genome using HGT-DB, a database of putative horizontally transferred genes in prokaryotes . As expected, the majority of predicted HTGs fall into the last two categories (nGCO, no homolog), but after removing HTGs from the complete gene set, the results were not affected (Additional file 2). However, this observation could be biased because the methodological approach used in HGT-DB to infer lateral gene transfer events, is largely dependent on GC content . The latter hypothesis could be explained by our finding that the last two categories of genes may be under weaker selective pressure than the first one and, consequently, accumulating a larger number of mutations, especially C-to-T mutations which are known to be the most common ones under neutral evolution . The observation that genomes of intracellular pathogens tend to be AT rich for energetic and resources availability reasons  could also explain the aforementioned result. After a speciation event occurs, some genes might remain GCO and continue to evolve slowly. This is probably the result of the strong evolutionary pressure to maintain their relative order, assisting the preservation of protein function or interaction with neighboring genes. On the other hand, other genes might lose their relative genomic position and start evolving faster. Genes in Salmonella with no homologs in E. coli K12 could either be HTGs or genes that have lost their genomic neighborhood and subsequently evolved to such an extent that no significant sequence similarities could be detected to support homology to any E. coli K12 gene.
The fate of duplicated genes is determined by gene order conservation
The most striking evidence that GCO genes evolve, on average, significantly slower than the nGCO genes, is inferred from an analysis of the subset of duplicated genes. We performed an all-against-all self-comparison of proteins encoded in the Salmonella genome and detected all groups of genes that could be assigned as homologs in the Salmonella genome that share the same best hit in the E. coli K12 genome (Additional file 3). We identified 687 such genes (15.5% of the complete Salmonella gene set) 343 of which are GCO (49.9%) and 344 are nGCO (51.1%). When compared to the same figures for the complete Salmonella gene set (68.3% and 12.6% respectively) the enrichment of the duplicate gene set in nGCO genes is evident. This enrichment probably takes place because, after a duplication event occurs, the selective pressure on one gene to retain its genomic neighborhood becomes less stringent. The proteins of GCO genes in the 343 duplicates share a 74.4% identity (standard deviation sd = 20.2), whereas for the 344 proteins of nGCO genes this figure drops to 37.0% (sd = 14.6; Wilcoxon rank-sum test: W = 106315.5, P-value = 0) (Fig. 1A). This result leads us to two major conclusions: First, as it may be deduced from a comparison of these identity percentages with the result for the complete genome set, the proteins encoded by this subset of duplicated genes evolve faster (in agreement with previous studies ). Second, whenever a gene duplication event occurs, the gene that retains its gene order tends to evolve more slowly than the one that travels away from the ancestral gene neighborhood and probably it is the former that keeps the original function. This finding complements an earlier study , although different experimental approaches have been employed here. Our results, even though based on the average conservation of putative homologs, corroborate the finding that genomic neighborhood conservation is an important additional criterion that should be taken into account in protein sequence similarity searches. We reached the same conclusions after calculating the Ka/Ks ratio for the two different duplicated gene groups - GCO and nGCO - with respective values 0.09 and 0.43 (Fig. 2). In most cases where all duplicated genes were nGCO, none of the genes exhibited particularly high identity to the common E. coli K12 homolog (Additional file 4). An analysis of the average GC content for the duplicated genes (GCO and nGCO) showed a similar pattern with the one of the overall genome (Fig. 1B).
Essential genes tend to conserve their order
H-NS preferentially regulates genes that do not conserve their order
Driven by recent results demonstrating that H-NS silences a significant amount of genes thought to have been acquired by lateral gene transfer, we calculated the number of GCO and nGCO genes in the dataset of 359 genes that were found to be silenced by the action of H-NS in the Salmonella chromosome . We ended up with the following numbers: 119 genes were GCO (33.1%), 99 (27.6%) were nGCO and 141 (39.3%) were without any detectable homolog in E. coli K12. The difference in the gene order status of genes compared to the overall genome is striking, with the representation being 68.3%, 12.6% and 19% respectively (see also fig. 3). This result demonstrates a preference of H-NS to repress genes that are either nGCO or that have no homologs in closely related species. The 119 GCO genes shared 74.7% identity and the nGCO 34.2% (P-value < 2.2e-16), a finding consistent with the results for both the overall genome set and the set of duplicated genes (Fig. 1A).
Gene order conservation of HNS repressed genes not predicted to be HTGs is associated to their GC content.
Gene order status
Number of Genes (%)
Average %GC content (sd)
No E. coli K12 homolog
In order to clarify whether the observed differences are due to pathogenicity related genes, we also compared Salmonella with an enteropathogenic strain of E. coli (O127:H6 str. E2348/69) (EPEC) ftp://ftp.ncbi.nih.gov/genomes/Bacteria/. We identified the complement of genes that had no homolog between Salmonella and E. coli K12 and had a homolog between Salmonella and EPEC (Additional file 5). Among the H-NS repressed genes within this dataset (14 genes out of 174 in total), we detected genes of Salmonella Pathogenicity Island-2 (SPI-2) such as ssaL, S , sseB and sscA . We also identified Salmonella genes whose order switches from nGCO to GCO when the reference genome is K12 and EPEC, respectively (Additional file 6). In this dataset, the H-NS repressed genes (11 genes out of 55 in total) include genes of SPI-2 such as ssaV, N, R, T, U .
Another interesting observation in the 359 H-NS repressed genes was the identification of 98 duplicated genes within this dataset (27.3% compared to 15.5% of duplicated genes in the whole genome) out of which only 29 were GCO. We subsequently analyzed the GC content for the duplicated genes of which only one paralog is targeted by H-NS. Of the 98 duplicated genes, a subset of 74 (out of which 22 were GCO) were identified to have 89 paralogs which are not H-NS repressed. After comparing the GC content of the above subsets of paralogs, we observed a striking difference. More specifically, the GC content of the 74 H-NS repressed genes was 46.5% (sd = 5.5) and for their 89 paralogs the GC content was 51.4% (sd = 4.2) (Wilcoxon rank-sum test: W = 1545, P-value = 5.663e-09). The above results provide a strong indication that, apart from repressing horizontally transferred genes, H-NS may also play a role in the transcriptional regulation of duplicated genes. Interestingly, genes that play an important role in the pathogenicity of Salmonella such as ssrB (essential for the expression of SPI-2 genes  genes) and ssaN, R, T, U and V (genes of SPI-2 that encode components of the second type III secretion apparatus ) were found to be nGCO, with low GC content (43.1 average GC%) whereas their corresponding duplicates were GCO with significantly higher GC content (54.79 average GC%). Moreover, the aforementioned virulence associated genes were identified to be repressed by H-NS , whereas their duplicates' expression was not significantly affected by H-NS.
Surprisingly, 20 genes out of those 359 were found to be essential for Salmonella. This paradox may be explained either by the growth conditions under which experiments where carried out  or by introducing H-NS as a part of a general, yet currently unknown, bacterial regulatory mechanism.
Taken together, this work shows that in Salmonella: (a) the proteins encoded by GCO genes tend to be more conserved (Fig. 1A and Fig. 2). Probably this is due to a correlation of conservation of gene order and the number of interacting proteins and/or expression levels of proteins encoded by genes belonging to the conserved clusters. Although it is known that protein expression levels are correlated to protein evolutionary rates [8, 9], and it is rather controversial whether there is a correlation between the connectivity of nodes in protein interaction networks and evolutionary rate [2, 7, 33–35], it still remains to be shown if any of these findings correlate to gene order conservation as well. (b) GCO genes have on average higher GC content when compared to genes that are nGCO and even higher than genes that do not share any homology to E. coli K12 genes (Fig. 1B). We speculate that this is a result of a mechanism that leads genes which evolve faster than others (and are not under strong selective pressure) to accumulate AT-rich mutations. (c) Genes that remain GCO have on average significantly lower Ka/Ks ratio than the nGCO ones, indicating that they are under higher selective pressure (Fig. 2). (d) Whenever a duplication event takes place, the duplicate that keeps its original order, is the one that keeps the highest sequence similarity (at least on average) and possibly the original function (in agreement to ). On the other hand, when the duplicated gene does not preserve its original order, it is subject to much faster evolution and less selective pressure as it is shown by comparing the respective Ka/Ks ratios (Fig. 2). Overrepresentation of nGCO genes in the duplicated group demonstrates that selective pressure on genes to keep their order is more relaxed after a duplication event. Interestingly, after a duplication event occurs and none of the paralogs retain their ancestral position in the genome, we failed to find any preference for sequence conservation (Additional file 4). (e) Finally, we demonstrated that the silencing mechanism via the H-NS protein in Salmonella significantly affects genes that are nGCO or genes that do not have any (detectable) homolog in E. coli K12. This could be another indication that H-NS might play a role, not only as a defensive instrument against foreign acquired DNA [12, 13, 36] but also as an internal control of native genes , as it could be of benefit to the organism to have them repressed for a variety of reasons associated with genome structure, for duplicated genes, non-essential genes or genes that did not retain their order.
In our analysis we tried to correlate gene order conservation with gene duplication, GC content and gene silencing in Salmonella enterica serovar Typhimurium LT2 based on two publications concerning H-NS silencing in the aforementioned species. We found that genes of conserved order not only evolve slower, as previously reported, but also tend to have higher GC content than the ones that do not conserve their order. We also found that essential genes tend to retain their genome position. Another finding was that after a duplication event takes place the gene that keeps its original position evolves slower than the one that looses it and probably keeps its primary function. Our study also shows that H-NS protein, a general repressor of a large number of genes in Salmonella, tends to avoid binding on genes with a conserved order. There is a clear indication that from the duplicated genes H-NS "prefers" to repress those ones that do not have a conserved gene order.
Definition of genes of conserved order
As a measure of conservation at the amino acid sequence level, we used the percentage of identical residues reported by BLASTP, while disregarding conservative substitutions and gaps. We follow the same criteria of gene order conservation as in . More specifically, given two genomes A and B encoding Na and Nb genes respectively, let us assume these genes are ordered a1, a2, ..., aNa and b1, b2, ..., bNb, respectively. Then, two genes ai and bj (1<i<Na, 1<j<Nb) are defined as GCO when the following two conditions are met: (1) ai, bj exhibit statistically significant sequence similarity; (2) at least one of ai-1, ai+1 exhibits statistically significant sequence similarity with one of bj-1, bj+1.
We applied a relatively strict E-value cut-off (E ≤ 10-6) and an additional requirement of 50% length coverage of both query and target sequences by the BLAST alignment. This approach was chosen in order to avoid spurious matches due to short conserved sequence motifs. The same criteria were applied both in the cross-genome comparison and in the self- comparison as presented in text. Differences from the results reported in  originate from the fact that we have used the latest versions of the E. coli K12 and Salmonella genomes, the difference in the E-value cut-off and the introduction of the alignment coverage criterion in this work.
We used the pairwise alignments reported by BLASTP to guide the construction of alignments of the corresponding coding regions, inserting in-frame gaps where necessary. For the Ka/Ks ratio calculation we used the yn00 program of the PAML package [25, 26] with the following parameters:
noisy = 1
icode = 10 * 0:universal code; 1:mammalian mt; 2-10:see below
weighting = 0 * weighting pathways between codons (0/1)?
commonf3 × 4 = 1 * use one set of codon freqs for all pairs (0/1)?
We have removed two genes (NP_462323 and NP_463455) for which the program couldn't provide us with a reliable Ka/Ks ratio, as well as all genes with Ka/Ks = 0 (Additional file 7). In order to avoid probable cases of saturated Ks values, where the estimated Ka/Ks ratio may be unreliable, we have further filtered our dataset to contain only those homologs with Ks<1.5 according to . Nevertheless, since sequences of nGCO genes on average seem to accumulate more non-synonymous substitutions than those of GCO genes, the difference in the Ka/Ks ratio between GCO and nGCO genes would probably be higher than the one reported here (Additional file 8, 9, 10.
All statistical calculations have been performed with R (Version 2.3.1) R Development Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, 2004. URL http://www.R-project.org. 3-900051-07-0.
We thank Christos Ouzounis (Kings College, London), Pantelis Georgiades (University of Cyprus) and Ioannis Kyrmitzoglou (University of Cyprus) for critically reading of the manuscript, useful discussions and suggestions. Funding to pay the Open Access publication charges for this article was provided by the University of Cyprus. We thank Mpriki for great inspiration. This paper is dedicated to the memory of Prof. Costas Kastritsis.
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