The Genom of Homo sapiens.pdf

154 PARKHILL AND THOMSONshow very high levels of similarity. This contrasts withthe fimbrial genes themselves, which are only weaklyconserved. Again, it seems likely that related gene setshave been exchanged at the same chromosomal locationby homologous recombination between the conservedflanking genes and exogenously acquired DNA.Pseudogenes and Gene LossThis long-term acquisition and exchange of genes hasbeen offset by recent gene loss, in the form of gene inactivationor pseudogene formation. The genome of S. Typhiwas predicted to contain over 200 pseudogenes, andthis number is almost certainly an underestimate, as thecriteria used to identify them were fairly stringent. Geneswere only suggested to be pseudogenes where they had amutation that would prevent correct translation, such asin-frame stop codons, frameshifts, deletions, or IS-elementinsertions. Clearly, genes can be functionally inactivatedin other ways, including promoter mutations andmis-sense coding changes, and these would probably notbe identified from sequencing alone.As described above, S. Typhi is host-restricted, and appearsto be only capable of infection of a human host,whereas S. Typhimurium, which causes a milder diseasein humans, has a much broader host range. After a carefulcomparison, S. Typhimurium was predicted to containonly around 39 pseudogenes (McClelland et al. 2001),compared to S. Typhi’s 204. It is apparent that the pseudogenesin S. Typhi are not randomly spread throughoutthe genome: They are overrepresented in genes that areunique to S. Typhi when compared to E. coli (59% of thepseudogenes lie in the unique regions, compared to 33%of all S. Typhi genes being unique), and many of the pseudogenesin S. Typhi have intact counterparts in S. Typhimuriumthat have been shown to be involved in aspectsof virulence and host interaction. Specific examplesof this include the leucine-rich repeat protein slrP (involvedin host-range specificity in S. Typhimurium [Tsoliset al. 1999] and secreted through a type III system),other type-III-secreted effector proteins including sseJ(Miao and Miller 2000), sopE2 (Bakshi et al. 2000), andsopA (Wood et al. 2000; Zhang et al. 2002), and the genesshdA, ratA, and sivH, which are present in an islandunique to Salmonellae infecting warm-blooded vertebrates(Kingsley and Baumler 2000). Many other inactivatedgenes may also have been involved in virulence orhost interaction, including components of seven of thetwelve chaperone-usher fimbrial systems. Given this distributionof pseudogenes, it is possible that the host specificityof S. Typhi may be due to the loss of an ability tointeract with a broader host range due to functional inactivationof the necessary genes. In contrast to other organismscontaining multiple pseudogenes, such as Mycobacteriumleprae (Cole et al. 2001), most of thepseudogenes in S. Typhi are caused by a single mutation,suggesting that they have been inactivated relatively recently.This is consistent with the fact that worldwide, S.Typhi is seen to be clonal (Reeves et al. 1989), and theserovar may be only a few tens of thousands of years old.It is apparent, therefore, that S. Typhi has recentlychanged its niche, from a gut organism with a broad hostrange to a systemic pathogen with a restricted host range.The ability to exploit this new niche is likely to havearisen through acquisition of novel genetic material, aspart of the long-term ebb and flow of genes that occursbetween members of the same or related species withinthis group of organisms. Such a niche change would, ofnecessity, have involved a small population of organisms,causing an evolutionary bottleneck. Such bottlenecks reducethe ability of competition and purifying selection toremove mutations from the population (Andersson andHughes 1996), and hence lead to an apparent rise in mutationrate, leaving the derived strain with many pseudogenes.The loss of these genes may have a short-term selectiveadvantage, or it may be selectively neutral. It isalso possible that some of the genes lost might have beenadvantageous in the longer term, but cannot now be recoveredby the organism.YERSINIA PESTIS , A VECTOR-ADAPTEDMAMMALIAN PATHOGENY. pestis, another member of the Enterobacteriaceae, isthe causative agent of plague, and as such has been responsiblefor an enormous amount of human mortalityover the last 1,500 years. As with S. Typhi, Y. pestis isalso near clonal in its world-wide spread, and thus has apparentlyvery recently emerged as a species. It has beenestimated that Y. pestis evolved from Y. pseudotuberculosis,which causes gastroenteritis, between 1,500 and20,000 years ago (Achtman et al. 1999). Therefore, Y.pestis has changed from being a gut bacterium (Y. pseudotuberculosis),transmitting via the fecal–oral route, toan organism capable of utilizing a flea vector for systemicinfection of a mammalian host (Perry and Fetherston1997; Achtman et al. 1999). As with S. Typhi, this changeis thought to be the result of a series of long-term gene acquisitions,culminating in the organism being in the positionto move into a new niche. Again, in taking this route,the organism appears to have gone through an evolutionarybottleneck, leading to pseudogene formation and, inthis case, IS element expansion.Gene Acquisition by YersiniaIt has been known for some time that Y. pestis has veryrecently acquired novel DNA in the form of plasmids. Y.pestis, Y. pseudotuberculosis, and Y. enterocolitica possessa 70-kb plasmid (pYV/pCD1 in Y. pestis and pIB1 inY. pseudotuberculosis) that encodes the Yop virulon, atype III secretion system essential for virulence in bothorganisms. Subsequently, Y. pestis has acquired twounique plasmids that encode a variety of other virulencedeterminants. The 9.5-kb plasmid (pPST/pPCP1) encodesthe plasminogen activator and putative invasin Pla(Cowan et al. 2000) which is essential for virulence by thesubcutaneous route. The 100- to 110-kb plasmid(pFra/pMT1) encodes the murine toxin (Ymt) and the F 1capsular protein, which have both been shown to play a