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. 2018 Aug 6;28(15):2420-2428.e10.
doi: 10.1016/j.cub.2018.05.058. Epub 2018 Jul 19.

Pan-genome Analysis of Ancient and Modern Salmonella Enterica Demonstrates Genomic Stability of the Invasive Para C Lineage for Millennia

Free PMC article

Pan-genome Analysis of Ancient and Modern Salmonella Enterica Demonstrates Genomic Stability of the Invasive Para C Lineage for Millennia

Zhemin Zhou et al. Curr Biol. .
Free PMC article


Salmonella enterica serovar Paratyphi C causes enteric (paratyphoid) fever in humans. Its presentation can range from asymptomatic infections of the blood stream to gastrointestinal or urinary tract infection or even a fatal septicemia [1]. Paratyphi C is very rare in Europe and North America except for occasional travelers from South and East Asia or Africa, where the disease is more common [2, 3]. However, early 20th-century observations in Eastern Europe [3, 4] suggest that Paratyphi C enteric fever may once have had a wide-ranging impact on human societies. Here, we describe a draft Paratyphi C genome (Ragna) recovered from the 800-year-old skeleton (SK152) of a young woman in Trondheim, Norway. Paratyphi C sequences were recovered from her teeth and bones, suggesting that she died of enteric fever and demonstrating that these bacteria have long caused invasive salmonellosis in Europeans. Comparative analyses against modern Salmonella genome sequences revealed that Paratyphi C is a clade within the Para C lineage, which also includes serovars Choleraesuis, Typhisuis, and Lomita. Although Paratyphi C only infects humans, Choleraesuis causes septicemia in pigs and boar [5] (and occasionally humans), and Typhisuis causes epidemic swine salmonellosis (chronic paratyphoid) in domestic pigs [2, 3]. These different host specificities likely evolved in Europe over the last ∼4,000 years since the time of their most recent common ancestor (tMRCA) and are possibly associated with the differential acquisitions of two genomic islands, SPI-6 and SPI-7. The tMRCAs of these bacterial clades coincide with the timing of pig domestication in Europe [6].

Keywords: Ancient DNA; Salmonella enterica; enteric fever; genomic stability; historical infections; host jump; pan-genome; paratyphoid fever; population genomics; tMRCA of bacterial pathogens.


Figure 1
Figure 1
Geographic, Archaeological, and Metagenomic Features of Skeleton SK152 (A) Excavation site (Folkebibilotekstomten, 1973–1985) of the church cemetery of St. Olav in Trondheim, Norway. The burial location of SK152 (red circle) belongs to a building phase that has been dated archaeologically [11] to 1200 CE (range 1175–1225). (B) Entire skeleton (top) and femoral long bone plus two teeth from which Salmonella DNA was extracted (bottom). (C) Map of Europe surrounding Norway (green) and location of Trondheim (red). (D) Deamination rate for metagenomic reads in the Salmonella Paratyphi C Ragna genome, human DNA and 11 single genome assemblies (Cxx) identified by Concoct [12]. C18 (Acidovorax) and C72 (Eubacterium) show high levels of deamination rates, as do reads from humans or Ragna, while the other assemblies have low levels and likely represent modern environmental bacteria. Data: Mean plus error bars showing standard deviations. See also Figure S2 for properties of aDNA reads.
Figure 2
Figure 2
Genomic Phylogenies of Salmonella enterica and the Para C Lineage (A) Maximum-likelihood phylogeny of 2,964 representative genomes of S. enterica subspecies enterica. Each genome is a representative of one ribosomal multi-locus sequence typing (rMLST) sequence type. Blue triangles indicate common lineages containing numerous genomes, including the Para C lineage. Several lineages are associated with common serovars, as indicated by horizontal labels. Red rectangle: Para C lineage plus the outgroup Birkenhead. (B) Pan-genomic contents for 6,665 pan-genes in 222 genomes of the Para C lineage, including Ragna, plus Birkenhead, with one stroke per gene. Circles (inner to outer); Circle 1: sixteen major, variably present chromosomal genomic islands (GI008–GI109) followed by sixteen cytoplasmic plasmids, circular phages plus one IME (PI01–PI16), color-coded as in the genomic islands key. Circles 2–10: the frequency of presence or absence of each gene per sub-lineage within the phylogram is indicated by color opacity. Circle 11: coverage of aDNA reads per gene within Ragna (scale 0–20 reads at 12:00). Circle 12: genes color-coded as in the genes key. Circle 13: traditional designations for GIs, PIs, and other variably present genomic elements (Table S3). Gray wedges: SPIs. See also Table S1 for summary statistics on the sources and dates of collection of the bacterial strains and Table S5 for the metadata for each individual genome.
Figure 3
Figure 3
Cartoon of the Evolutionary History of the Para C Lineage on a Time Frame for Human History in Europe BP: before present. The tree is annotated with the acquisitions of the virulence plasmid (VirP), SPI-6 and SPI-7 as annotated by inward arrows, and deletions of parts of SPI-6 as annotated by outward arrows. Numbers in blue indicate date estimates and their 95% credible intervals (parentheses) according to a Bayesian phylogenetic approach. Red numbers indicate numbers of substitution events for non-recombinant core SNPs except for Lomita and Birkenhead, where they indicate total core SNPs. The host specificities of the individual serovars are indicated by cartoons at the right. See also Figure S3 for the timing of individual changes in pseudogenes and gene gain/loss, Figure S4 for the locations of variable genes by lineage within SPI-6, Table S3 for the properties of individual genomic islands, and Table S4 for detailed estimates of tMRCAs. See also Table S2.

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