The Genom of Homo sapiens.pdf

156 PARKHILL AND THOMSONGene Loss and IS-element Expansion in Y. pestisAt the time of publication, Y. pestis CO92 was predictedto encode 149 pseudogenes, although for the reasonsdescribed above, this is likely to be an underestimate.In addition to pseudogene formation by pointmutation, many genes have been inactivated by IS-elementinsertion. IS (insertion sequence) elements are smallmobile elements that carry genes only for their own transposition,and can thus be considered to be selfish parasiticelements within the genome. Y. pestis has undergone atenfold expansion in IS elements since separating from Y.pseudotuberculosis (Odaert et al. 1996; McDonough andHare 1997), and it appears that this expansion of IS elementscan be attributed to the same evolutionary processesas the increase in point mutations. During normalbacterial growth, IS elements will be actively transposingat a low rate and inserting into new chromosomal loci. Ina large, freely recombining population, most of theseevents will be removed by competition and selection.However, as described above, during an evolutionarybottleneck many of these lesions will not be removed, dueto the reduced level of purifying selection, and will becomefixed. The result is an apparent increase in IS elementsin the daughter populations.Analysis of the pattern of gene loss revealed that it wasnot spread randomly among all classes of genes, but thatpseudogenes were specifically over- and underrepresentedin particular functional classes (Fig. 4). Pseudogenes areunderrepresented in classes involved in central and intermediarymetabolism, indicating that the core functions ofthe organism have been maintained. Conversely, manygenes involved in pathogenicity and host interaction havebeen inactivated. This may seem counterintuitive, giventhat Y. pestis is a more virulent pathogen than its immediateancestor, but closer examination reveals that many ofthese genes were specifically involved in pathogenicity viathe fecal–oral route and are likely to be unnecessary, or indeeda hindrance, for systemic infection and spread. An exampleof this is the yadA and inv genes, the products ofwhich encode an adhesin and an invasin, which are importantfor adherence to surfaces of the gut and the invasion ofthe cells lining it (Pepe and Miller 1993; El Tahir andSkurnik 2001). Replacement of the mutated yadA genewith an intact version in Y. pestis has been shown to resultin a significant decrease in virulence by the subcutaneousinfection route (Rosqvist et al. 1988). In addition to yadAand inv, many of the pseudogenes were also predicted toencode other adhesin-like molecules that may also havebeen important for enteropathogenicity.The second largest group of pseudogenes was predictedto encode surface-exposed or exported proteins. Fivepseudogenes were in the lipopolysaccharide (LPS)biosynthesis operon. The LPS O-side chain plays a keyrole in the virulence of a range of pathogens including Y.enterocolitica (Darwin and Miller 1999). The O-sidechain is known to mediate resistance to complement-mediatedand phagocyte killing, and it might also play a roleFigure 4. Proportion of genes and pseudogenes in Y. pestis in different functional categories. The graph shows the percentage of allgenes (in white), and pseudogenes (in gray) in each of the functional categories. (Adapted from Parkhill et al. 2001b.)