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Genome Structure of Mycobacteriophage D29: Implications for Phage Evolution Michael E

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Genome Structure of Mycobacteriophage D29: Implications for Phage Evolution Michael E J. Mol. Biol. (1998) 279, 143±164 Genome Structure of Mycobacteriophage D29: Implications for Phage Evolution Michael E. Ford, Gary J. Sarkis, Aimee E. Belanger, Roger W. Hendrix andGrahamF.Hatfull* The Pittsburgh Bacteriophage Mycobacteriophage D29 is a lytic phage that infects both fast and slow- Institute and Department of growing mycobacterial species. The complete genome sequence of D29 Biological Sciences, University reveals that it is a close relative of the temperate mycobacteriophage L5, of Pittsburgh, Pittsburgh whose sequence has been described previously. The overall organization PA 15260, USA of the D29 genome is similar to that of L5, although a 3.6 kb deletion removing the repressor gene accounts for the inability of D29 to form lysogens. Comparison of the two genomes shows that they are punctu- ated by a large number of insertions, deletions, and substitutions of genes, consistent with the genetic mosaicism of lambdoid phages. # 1998 Academic Press Limited Keywords: mycobacteriophage; bacteriophage evolution; DNA sequence; *Corresponding author genome organization; lysogeny Introduction (Oyaski&Hatfull,1992).Althoughtemperate,L5 encodes a DNA polymerase, tRNAs, and ribonu- The resurgence of tuberculosis in the United cleotide reductase, features commonly associated States and the prevalence of drug-resistant strains withthelyticphagessuchasT4(Broida& of Mycobacterium tuberculosis present considerable Abelson,1985).Interestingly,L5sharesanother publichealthconcerns(Bloom&Murray,1992). attribute with lytic phages, the ability to inhibit Unfortunately, the genetics of the mycobacteria are hostgeneexpressionduringlyticgrowth(Hatfull not well understood although signi®cant advances &Sarkis,1993).WhiletheidentitiesofmanyL5 havebeenmadeinrecentyears(Hatfulletal., genes remain unknown, the genes encoding a 1994).Thestudyofmycobacteriophageshaspro- number of the proteins which comprise the phage ven particularly useful in the development of virion were revealed by amino-terminal sequences mycobacterial genetics. Mycobacteriophages are (Hatfull&Sarkis,1993).Additionally,functional useful systems for characterizing their hosts and studies showed that the product of gene 33 (gp33) have been helpful in establishing mycobacterial isthephageintegrase(Leeetal.,1991),andgp71is geneticsystems(Hatfull&Jacobs,1994). the phage repressor responsible for maintenance of Mycobacteriophage L5 is the best characterized lysogenyandsuperinfectionimmunity(Donnelly- ofthemycobacteriophages(Hatfull,1994).L5isa Wuetal.,1993). temperate phage isolated from a strain of Mycobac- The protein encoded by gene 71 has been shown teriumsmegmatisbyDoke(1960)thatformsstable to bind to DNA and its binding site has been lysogens in which the phage genome is integrated de®ned. Many such sites are scattered throughout intothebacterialattachmentsite,attB(Snapper the L5 genome, and low levels of transcription in etal.,1988;Leeetal.,1991).L5alsoinfectsslow- the L5 prophage may be maintained via the bind- growing mycobacteria such as Mycobacterium bovis ingofgp71tothesesites(Brownetal.,1997).In bacille Calmette-GueÂrin (BCG), although rather addition, several L5 promoters have been located speci®c conditions are required for ef®cient infec- and studied, including those involved in modulat- tion(Fullner&Hatfull,1997). ing early growth and repressor transcription The complete DNA sequence of the L5 genome (Nesbitetal.,1995).Therepressorproteinbindsto hasbeendetermined(Hatfull&Sarkis,1993).The an operator site overlapping the early lytic promo- genome of L5 is 52,297 bp long, composed of 85 ter P , thereby maintaining stable L5 lysogeny protein-codingandthreetRNAgenes(Hatfull& left (Nesbitetal.,1995;Brownetal.,1997).Addition- Sarkis,1993),andterminatedincohesiveends ally, gp71 regulates its own synthesis by binding to a relatively weak binding site upstream of gene Abbreviations used: PFU, plaque-forming units. 71, modulating transcription from three promoters 0022±2836/98/210143±22 $25.00/0/mb971610 # 1998 Academic Press Limited 144 Mycobacteriophage D29 (P1, P2, and P3) in the gene 71-72 intergenic region recombinationevents that do not affect the viabili- (Nesbitetal.,1995).Little is known about the ty of the resulting viruses survive. Therefore, such location of signals responsible for late lytic gene transition sites between matching and non-match- expression. ing sequences of two phage genomes are witnessed Studies of mycobacteriophages have bene®ted most often at gene boundaries or at the boundaries mycobacterial genetics in a number of ways of functional clusters of genes. However, (Hatfull,1994).First,integration-pro®cient vectors additional examples are occasionally found within containing the L5 int gene and attachment site genes,atdomainboundaries(Casjensetal.,1992). (attP) have been constructed which ef®ciently Mycobacteriophage evolution could be studied transform M. smegmatis and the vaccine strain by comparing the genome of L5 to that of another M.bovisBCG(Leeetal.,1991). These plasmids have closely related mycobacteriophage. Therefore, we beenusedtoidentifyvirulencegenes(Pascopella determined the complete DNA sequence of myco- etal., 1994) and have proven useful in the pro- bacteriophage D29. D29 was ®rst isolated from ductionofrecombinantBCGvaccines(Stoveretal., soil, and shown to be active against Mycobacterium 1991).Inaddition,theL5 repressor gene has been tuberculosis(Fromanetal.,1954).Theplaquespro- successfully employed as a selectable marker for duced on the tubercle bacillus were clear, indicat- plasmid maintenance without the use of antibiotic ing that D29 is a lytic phage (i.e. incapable of resistancemarkers(Donnelly-Wuetal.,1993). lysogeny). Studies of D29 suggest that it is a mem- Recombinant L5 phages containing a copy of the ber of the ``L5-like'' family of mycobacteriophages. ®re¯y gene (FFlux) have been created and shown Although lytic, D29 is subject to superinfection to be very effective for the rapid determination of immunity by L5; in other words, it is incapable of antibioticsusceptibilitypatterns of mycobacterial infecting an L5 lysogen of M. smegmatis. Only the isolates(Sarkisetal.,1995).Similarreporterphages product of L5 gene 71 is required to prevent infec- based on TM4 and D29 have also been described tion of M. smegmatis by D29, demonstrating that (Jacobsetal.,1993;Pearsonetal.,1996).Recently, it this is true immunity rather than exclusion has been shown that mycobacteriophages hold (Donnelly-Wuetal.,1993).Inadditiontothe considerable promise as tools for transposon deliv- shared immunity of L5 and D29, these phages eryinmycobacteria(Bardarovetal.,1997). appear to have a common mode of entry in In addition to the clues that were provided M. smegmatis. In particular, overexpression of the about its life cycle, several other interesting obser- M. smegmatis mpr gene confers resistance to both vations were brought to light by the sequencing of L5 and D29, but not to other mycobacteriophages L5. Although L5 shares absolutely no discernible (Barsom&Hatfull,1996).The identity of the recep- sequence similarity, at either the DNA or the tor used for adsorption of these phages is not clear, amino acid levels, with lambdoid phages, some although pyruvylated, glycosylated acyltrehaloses elements of the arrangement of its head and tail have been implicated in the infection of M. smeg- genes are reminiscent of phages such as lambda matisbyD29(Besraetal.,1994).Additionally,the andP22(Casjensetal.,1992).Additionally,L5 two phages have similar host ranges (our unpub- apparently forms covalent crosslinks among all lished observations), though there are some differ- copies of its major head subunit during formation encesininfectionrequirements(Fullner&Hatfull, oftheviralcapsid(Hatfull & Sarkis, 1993; Hatfull 1997),andD29hasbeenreportedtoadsorbto &Jacobs,1994),somethingpreviouslydocumented Mycobacteriumleprae(Davidetal.,1984).Finally, only in the lambdoid coliphage HK97 (Popa et al., DNA hybridization studies showed that the D29 1991;Dudaetal.,1995).Finally, a programmed and L5 genomes are closely related (M. Donnelly- translational frameshift that has been shown to Wu & G.F.H., unpublished observations), although take place in lambda between genes G and T of the they show different patterns of fragments for many tailgenecluster(Levinetal.,1993)alsoappearsto restrictionenzymes(Lazraqetal.,1989;Oyaski& occur in the analogous regions of HK97 and L5 Hatfull,1992). (Casjensetal.,1992;Hatfull&Jacobs,1994), Here we describe the complete DNA sequence of although these three phages show no sequence the genome of mycobacteriophage D29, compare similarity in this area of their genomes. the genetic map obtained from it with that already Studies of members of the lambdoid group of determined for L5, and consider the consequences bacteriophages have noted that the genomes of for bacteriophage evolution previously only inten- these phages appear to be genetic mosaics. In other sively studied in the lambdoid family of phages. words, highly similar segments of any two gen- Some genetic explanations for observed phenotypic omes are often separated by sharp transitions from differences between L5 and D29 are given. adjacent segments that match each other at a differentlevelofsimilarity ornotatall.Casjens et al.(1992)takethe appearanceofsuchdistinct Results boundaries between genome segments as evidence Analysis of D29 particles of multiple recombination events within the evol- utionary histories of the phages that display then. While the morphology
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