Comparative genomic analysis of Streptococcus suis reveals significant genomic diversity among different serotypes
- Anding Zhang†1, 3,
- Ming Yang†2,
- Pan Hu†3,
- Jiayan Wu2,
- Bo Chen3,
- Yafeng Hua3,
- Jun Yu2,
- Huanchun Chen1, 3,
- Jingfa Xiao2Email author and
- Meilin Jin1, 3Email author
© Zhang et al; licensee BioMed Central Ltd. 2011
Received: 20 June 2011
Accepted: 25 October 2011
Published: 25 October 2011
Streptococcus suis (S. suis) is a major swine pathogen and an emerging zoonotic agent. Serotypes 1, 2, 3, 7, 9, 14 and 1/2 are the most prevalent serotypes of this pathogen. However, almost all studies were carried out on serotype 2 strains. Therefore, characterization of genomic features of other serotypes will be required to better understand their virulence potential and phylogenetic relationships among different serotypes.
Four Chinese S. suis strains belonging to serotypes 1, 7, 9 and 1/2 were sequenced using a rapid, high-throughput approach. Based on the 13 corresponding serotype strains, including 9 previously completed genomes of this bacterium, a full comparative genomic analysis was performed. The results provide evidence that (i) the pan-genome of this species is open and the size increases with addition of new sequenced genomes, (ii) strains of serotypes 1, 3, 7 and 9 are phylogenetically distinct from serotype 2 strains, but all serotype 2 strains, plus the serotype 1/2 and 14 strains, are very closely related. (iii) all these strains, except for the serotype 1 strain, could harbor a recombinant site for a pathogenic island (89 K) mediated by conjugal transfer, and may have the ability to gain the 89 K sequence.
There is significant genomic diversity among different strains in S. suis, and the gain and loss of large amount of genes are involved in shaping their genomes. This is indicated by (i) pairwise gene content comparisons between every pair of these strains, (ii) the open pan-genome of this species, (iii) the observed indels, invertions and rearrangements in the collinearity analysis. Phylogenetic relationships may be associated with serotype, as serotype 2 strains are closely related and distinct from other serotypes like 1, 3, 7 and 9, but more strains need to be sequenced to confirm this.
Streptococcus suis (S. suis) is a major swine pathogen responsible for severe economic losses in the pork industry and is emerging as an important threat to human health, especially to people who have close contact with swine or pork by-products [1–3]. Since the first reported case of human meningitis caused by S. suis in Denmark in 1968, cases of infection have been reported continuously in more than 20 countries, with more than 700 people being affected . Two recent large-scale outbreaks of human S. suis infections in China (one associated with 25 cases and 14 deaths in Jiangsu in 1998 and the other with 204 cases and 38 deaths in Sichuan in 2005) have raised awareness of the existing threat to public health [5–9]. The infection has also caused sporadic human illness in other countries, including Thailand [10–12], the United Kingdom , Portugal , Italy , Japan , Australia , the Netherlands  and the United States [19–22].
S. suis is an encapsulated Gram-positive coccus that possesses cell wall antigenic determinants, similar to Lancefield group D . Among the 33 serotypes that have been classified based on the composition of their capsular polysaccharides (CPS), only a limited number are responsible for infections in pigs, including serotypes 1-9 and 14 . Although the distribution of different serotypes varies depending on the geographical origins of the strains, S. suis serotype 2 (SS2) is considered the most pathogenic and the most prevalent capsular type among diseased pigs, followed by serotypes 3 and 1/2 [25, 26]. Serotypes 1, 7 and 9 are also prevalent in several European [27, 28] and Asian countries . Serotype 14 infections in humans are now being reported with increasing frequency [29, 30]. However, little information about these prevalent serotypes is available, except for serotype 2. Comparative genomic analysis is a powerful method for exploring the relationships between genotypes and phenotypes and for discovering genetic markers for clinical purposes.
A previous comparative genomic study based on examination of an intermediately pathogenic strain (89/1591), a highly pathogenic strain (GZ1) and an epidemic strain (SC84) indicates that acquiring particular genomic islands is essential for the evolution of highly pathogenic bacteria , and a specific pathogenic island (89 K) is found to be an essential component of virulent Chinese SS2 isolates [31, 32]. A recent study indicates that the pathogenic island (89 K) can exhibit spontaneous excision to form an extrachromosomal circular product, which can then undergo lateral transfer to a recipient strain through site-specific recombination . To understand the evolution of virulence in other prevalent serotypes, it is important to know whether they could also harbor recombinant target sites and serve as recipients for exogenous sequences.
In this study, we sequenced the genomes of 4 prevalent S. suis serotypes: 1, 1/2, 7 and 9. By taking the publicly available complete genome sequences of serotypes 2, 3 and 14 as the reference, a comparative genomic analysis was performed to provide a global genomic characterization of this prevalent pathogenic bacterium. Acquisitions and losses of genome components were identified, and different genes involved in CPS biosynthesis were found to be serotype determinants. The study also indicated that serotypes 1/2, 2, 3, 7 and 9, but not serotype 1, could supply a recombinant site for a pathogenic island (89 K) mediated by conjugal transfer, which suggests that these serotypes are able to obtain the 89 K sequence and thus become more virulent.
Results and Discussion
General features of the sequenced genomes
Among the 33 known serotypes, serotypes 1, 2, 3, 7, 9 and 1/2 are the most prevalent in pigs, and the strains causing human infections were also found among these serotypes [24–28]. Although 8 genome sequences of strains from serotype 2 were available, there was little information about the other serotypes, except for our recently updated genome sequences for serotypes 3  and 14 . In this study, whole genome sequencing was performed on 4 prevalent Chinese S. suis strains belonging to serotypes 1, 7, 9 and 1/2. Each of the 4 genomes was sequenced to a high level of redundancy (sequencing depth was 722 to 1627 fold). We filtered low-quality reads and used only high-quality reads for assembly. Reads for each genome were assembled into scaffolds, with 26 to 94 large scaffolds (>500bp) obtained per genome. Then scaffolds were aligned to the published genomes of S. suis to obtain linkage information for gap closure. All 4 annotated complete genomes were deposited in GenBank.
General genome features and assembly statistics for each strain
Pseudogenes & Partial Genes
Avg. Gene Length (nt)
Scaffold N50 (kb)
Identification of gene clusters
Core and pan-genome analysis of S. suis
S. suis core genome
S. suis pan-genome analysis
To determine whether the S. suis pan-genome was open, the number of new genes (unique genes) was calculated every time a new genome was incorporated. As expected, the observed numbers varied greatly, as shown in Figure 4B. The large deviation from the mean suggested high levels of variation within S. suis. The mean values of new genes were used to perform the extrapolation. Similar to the core genes, the plot of new genes was fit well by a decaying function, and remarkably, the extrapolated curve reached an asymptotic value of 82, which meant that every newly sequenced genome could bring 82 new genes on average, even if many genomes were sequenced. This finding revealed that the species possesses an open pan-genome for which the size increases with the addition of new sequenced strains (Figure 4C). This was consistent with a previous study on the core and pan-genome of Streptococcus, which indicated that S. suis was the lineage with the largest number of gene gains and losses .
Phylogenetic relationships among different serotype strains
Genomic arrangement of S. suis strains
Genes involved in CPS biosynthesis
The prevalent serotypes supply a potential recombinant site for a pathogenic island (89 K)
The two large-scale outbreaks in China in 1998 and 2005 prompted researchers to determine which changes in the S. suis genome make it so highly virulent. Using comparative genomic analysis, an 89-kb sequence was identified only in the Chinese epidemic strain . The subsequent investigation indicated that the 89-kb represented a GI-type T4SS-mediated horizontal transfer of a pathogenicity island that could be transferred to the recipient strain through a 15-bp sequence specific recombination event, although the transfer could be successfully observed only to serotype 2 . Because the 89-kb harbored necessary elements for horizontal transfer, such as integrase, excisionase, DNA relaxase and so on, suggesting that this pathogenicity island maintained the potential to transfer to the recipient strain harboring the 15-bp sequence. The Genomic analysis indicated that the pathogenicity island did not exist in the other sequenced prevalent serotypes and such a 15-bp sequence could be found in the genomes of sequenced serotypes 1/2, 2, 3, 7 and 9, but not in serotype 1. More surprisingly, the flanking sequence structure of the 89 K region in the epidemic strain SC84 showed high similarity with the other sequenced serotypes, suggesting that these prevalent serotypes harboring the site for homologous recombination (the 15-bp sequence) would have the potential to act as recipient strains for the pathogenic island from the epidemic strain.
In summary, comparative genomic analysis using genome sequences originating from prevalent S. suis serotypes showed that the observed pan genome of S. suis consists of 3585 gene clusters composed of 1343 core genome genes, 1031 distributed genes and 1211 strain-specific genes. The species possesses an open pan-genome and is the Streptococcus lineage with the greatest number of gene gains and losses. The results of this study also indicate that the other serotypes could supply a recombinant site for a pathogenic island (89 K) mediated by conjugal transfer, which suggests that these serotypes have the potential to obtain an 89 K sequence, and thus become more virulent. Our findings could be contributed to a better understanding of the genomics of S. suis.
Sequenced strains and genomes available in GenBank used in this study
Place of origin
GenBank accession number
Our other study a
Sequencing and assembly
Bacterial genomes were sequenced at the Beijing Institute of Genomics (China) using a whole-genome shotgun sequencing strategy and Illumina Genome Analyzer sequencing technology. For each sample, a paired-end sequencing library containing fragments of approximate 500 bp was constructed. The short reads were filtered for quality and assembled with SOAPdenovo (http://soap.genomics.org.cn/soapdenovo.html). To fill the intra-scaffolds gaps, we used paired-end information to retrieve read pairs that had one read that was aligned to the contigs and another read that was located in the gap region. With this information, we did a local assembly for the collected reads. Then, these scaffolds were ordered relative to the genome of S. suis strain 05ZYH33 (deposited in the NCBI database; GenBank accession number CP000407) using MUMmer3 . Gaps were closed by primer walking and sequencing of PCR products. Possible misassemblies were corrected using PCR amplification and direct sequencing. Sequences were edited in Consed .
Initially, Open Reading Frame (ORF) prediction was performed using Glimmer3  and Genemarks , and the results were amalgamated. To avoid possible missing coding sequences, entire DNA sequences were compared to all known protein sequences from other published S. suis strains using BLAST searches. Then, all predicted ORFs were translated into amino acid sequences and compared against the non-redundant protein (nr) database using the BLASTp program, with a maximum expectation value of 1 × 10-6. ORFs with no BLAST hit to any other protein were automatically annotated as "hypothetical proteins." tRNAs and rRNAs were identified using tRNAscan-SE  and RNAmmer1.2 , respectively. Insertion sequence (IS) elements were found with IS Finder . Genome islands (GIs) were identified using IslandViewer , which integrates three different genomic island prediction methods, followed by manual inspection.
The four annotated complete genome sequences have been deposited in GenBank with the accession numbers CP002640 (SS12), CP002641 (D9), CP002644 (D12) and CP002651 (ST1).
Whole genome alignment and ortholog identification
Multiple genome alignments for 13 completely sequenced strains were constructed and visualized using the progressive Mauve program in Mauve v2.3.1  at default settings.
All CDSs were extracted from the 13 S. suis genomes, and they were grouped into homologous clusters using InParanoid4 [51–53], which employs a BLAST reciprocal best hit algorithm, with default parameters.
Core and pan-genome analysis
Tables of homologous clusters from InParanoid4 were compiled for identifying shared and unique genes. The numbers of conserved genes and unique genes depend on how many strains are taken into account. Thirteen strains with complete genome sequences were simulated in all possible combinations. The sizes of the core genome and novel gene set were calculated for each combination and then extrapolated using several functions to find a best fit from the mean number at each sampling point .
Phylogenetic trees of S. suis strains were constructed using two different methods . The first utilized multiple sequence alignments of 522 single-copy core genes with nearly identical lengths and exactly one member in each of the compared strains. The alignments of these genes were concatenated into one large sequence alignment with a length of 457779 bp, and a phylogenetic tree was reconstructed using MrBayes 3 [56, 57] (200,000 generations, sampled every 100 generations with a gamma distribution model and invariant class). The second method was based on the presence or absence of genes in the pan-genome. Genetic distances were defined as Σ n | g n, i - g n, k |, where g n, i is 1 if gene n is present in strain i and is zero otherwise. A dendrogram was generated using the UPGMA (unweighted pair group method with arithmetic mean) method implemented in the Phylip package .
This study was supported by 973 Program (2011CB106535), 863 Program (2011AA10A210), the National Major Program of Science & Technology (2008ZX10004-013, 2009ZX10602-14), the National Transgenic Major Program (2009ZX08009-141B), Special Fund for Public Welfare Industry of Chinese Ministry of Agriculture (200803016) and Innovative Research Team in University (IRT0726).
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