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Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi
Author: C. Frasier
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"Nature � Macmillan Publishers Ltd 1997 articles 580 NATURE | VOL 390 | 11 DECEMBER 1997 Genomic sequence of a Lyme disease spirochaete, Borrelia burgdorferi Claire M. Fraser*, Sherwood Casjens?, Wai Mun Huang?, Granger G. Sutton*, Rebecca Clayton*, Raju Lathigra?, Owen White*, Karen A. Ketchum*, Robert Dodson*, Erin K. Hickey*, Michelle Gwinn*, Brian Dougherty*, Jean-Francois Tomb*, Robert D. Fleischmann*, Delwood Richardson*, Jeremy Peterson*, Anthony R. Kerlavage*, John Quackenbush*, Steven Salzberg*, Mark Hanson?, Rene van Vugt?, Nanette Palmer?, Mark D. Adams*, Jeannine Gocayne*, Janice Weidman*, Teresa Utterback*, Larry Watthey*, Lisa McDonald*, Patricia Artiach*, Cheryl Bowman*, Stacey Garland*, Claire Fujii*, Matthew D. Cotton*, Kurt Horst*, Kevin Roberts*, Bonnie Hatch*, Hamilton O. Smith* & J. Craig Venter* * The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, Maryland 20850, USA ? Division of Molecular Biology and Genetics, Department of Oncological Sciences, University of Utah, Salt Lake City, Utah 84132, USA ? MedImmune, Inc., 35 West Watkins Mill Road, Gaithersburg, Maryland 20878, USA ........................................................................................................................................................................................................................................................ The genome of the bacterium Borrelia burgdorferi B31, the aetiologic agent of Lyme disease, contains a linear chromosome of 910,725 base pairs and at least 17 linear and circular plasmids with a combined size of more than 533,000 base pairs. The chromosome contains 853 genes encoding a basic set of proteins for DNA replication, transcription, translation, solute transport and energy metabolism, but, like Mycoplasma genitalium, it contains no genes for cellular biosynthetic reactions. Because B. burgdorferi and M. genitalium are distantly related eubacteria, we suggest that their limited metabolic capacities reflect convergent evolution by gene loss from more metabolically competent progenitors. Of 430 genes on 11 plasmids, most have no known biological function; 39% of plasmid genes are paralogues that form 47 gene families. The biological significance of the multiple plasmid-encoded genes is not clear, although they may be involved in antigenic variation or immune evasion. In the mid-1970s, a geographic clustering of an unusual rheumatoid arthritis-like condition was reported in Connecticut 1 . That cluster of cases focused attention on the syndrome that is now called Lyme disease. It was subsequently realized that a similar disorder had been known in Europe since the beginning of this century. Lyme disease is characterized by some or all of the following manifestations: an initial erythematous annular rash, ?flu-like symptoms, neurological complications, and arthritis in about 50% of untreated patients 2 .In the United States, the disease occurs primarily in northeastern and midwestern states, and in western parts of California and Oregon. These regions coincide with the ranges of various species of Ixodes ticks, the primary vector of Lyme disease. Lyme disease is now the most common tick-transmitted illness in the United States, and has been reported in many temperate parts of the Northern Hemisphere. It was not until the early 1980s that a new spirochaete, Borrelia burgdorferi 3 , was isolated and cultured from the midgut of Ixodes ticks, and subsequently from patients with Lyme disease 4,5 . Analysis of genetic diversity among individual Borrelia isolates has defined a closely related cluster containing at least 10 tick-borne species of Lyme disease agents, called ?B. burgdorferi (sensu lato)?. B. burgdor- feri resembles most other spirochaetes in that it is a highly specialized, motile, two-membrane, spiral-shaped bacterium that lives primarily as an extracellular pathogen. Borrelia is fastidious and difficult to culture in vitro, requiring a specially enriched media and low oxygen tension 6 . One of the most striking features of B. burgdorferi is its unusual genome, which includes a linear chromosome approximately one megabase in size 7?10 and numerous linear and circular plasmids 11?13 , with some isolates containing up to 20 different plasmids. The plasmids have a copy number of approximately one per chromo- some 10,14 , and different plasmids often appear to share regions of homologous DNA 13,15,16 . Long-term culture of B. burgdorferi results in the loss of some plasmids, changes in protein expression profiles, and a loss in the ability of the organism to infect laboratory animals, suggesting that the plasmids encode important proteins involved in virulence 17?19 . Because of its importance as a pathogen of humans and animals, and the value of complete genome sequence information for under- standing its life cycle and advancing drug and vaccine development, we sequenced the genome of B. burgdorferi type strain (B31), using the random sequencing method previously described 20?24 .Herewe summarize the results from sequencing, assembly and analysis of the linear chromosome and 11 plasmids. Chromosome analysis The linear chromosome of B. burgdorferi has 910,725 base pairs (bp) and an average G+C content of 28.6%. Base pair one represents the first double-stranded base pair that we observed at the left telomere. Previous genome characterizations agree with the nucleotide sequence of the large chromosome 10,25?28 . The 853 predicted coding sequences (open reading frames; ORFs) have an average size of 992 bp, similar to that observed in other prokaryotic genomes, with 93% of the B. burgdorferi genome representing Figure 1 Linear representations of the B. burgdorferi B31 chromosome and plasmids. The location of predicted coding regions colour-coded by biological role, RNA genes, and tRNAs is indicated. Arrows represent the direction of transcription for each predicted coding region. Numbers associated with tRNA symbols represent the number of tRNAs at a locus. Numbers associated with GES represent the number of membrane-spanning domains according to the Goldman, Engelman and Steitz scale as calculated by TopPred 49 . Only proteins with five or more GES are indicated. Members of paralogous gene families are identified by family number. Transporter abbreviations: mal, maltose; P, gly and bet, proline, glycine, betaine; glyc, glycerol; aa, amino acid; E, glutamate; fru, fructose; glu, glucose; s/p, spermidine/putrescine; pan, pantothenate; Pi, phos- phate; lac, lactate; rib, ribose; ?, unknown. Q Nature � Macmillan Publishers Ltd 1997 articles NATURE | VOL 390 | 11 DECEMBER 1997 581 coding sequence. Biological roles were assigned to 59% of the 853 ORFs using the classification scheme adapted from Riley 29 (Fig. 1), 12% of ORFs matched hypothetical coding sequences of unknown function from other organisms, and 29% were new genes. The average relative molecular mass (M r ) of the chromosome-encoded proteins in B. burgdorferi is 37,529 ranging from 3,369 to 254,242, values similar to those observed in other bacteria including Haemophilus influenzae 20 and Mycoplasma genitalium 21 . The median isoelectric point (pI) for all predicted proteins is 9.7. Analysis of codon usage in B. burgdorferi reveals that all 61 triplet codons are used. When both AU- and GC-containing codons specify a single amino acid, there is a marked bias (from 2-fold to more than 20-fold, depending on the amino acid) in the use of AU- rich codons. The most frequently used codons are AAA (Lys, 8.1%), AAU (Asn, 5.9%), AUU (Ile, 5.9%), UUU (Phe, 5.7%), GAA (Glu, 5.0%), GAU (Asp, 4.2%) and UUA (Leu, 4.2%). The most common amino acids are Ile (10.6%), Leu (10.3%), Lys (10.2%), Ser (7.8%) and Asn (7.2%). The high value for Lys is in agreement with the median calculated isoelectric point of 9.7. Plasmid analysis Analysis of the nucleotide sequence and Southern analyses on B. burgdorferi DNA indicate that, in addition to the large linear chromosome, isolate B31 contains linear plasmids of the following approximate sizes: 56 kilobase pairs (kbp) (lp56), 54 kbp (lp54), four plasmids of 28 kbp (lp28-1, lp28-2, lp28-3 and lp28-4), 38 kbp (lp38), 36 kbp (lp36), 25 kbp (lp25) and 17 kbp (lp17); and circular plasmids of the following sizes: 9 kbp (cp9), 26 kbp (cp26) and five or six homologous plasmids of 32 kbp (cp32). These include all of the plasmids previously identified in this strain, but comparisons with other B31 cultures suggest that this isolate may have lost one 21 kbp linear and one or two 32 kbp circular plasmids during growth in culture since its original isolation 11?14,19,30 . The sequences of all plasmids were assembled as part of this project. However, the assembled sequences of the cp32 and related lp56 plasmids could not be determined with a high degree of confidence because of DNA sequence similarity among them ($99% in several regions of 3,000?5,000 bp per plasmid) 13,16 (Table 1). Improved assembly strategies are being tested to achieve closure on these plasmids (G. Sutton, unpublished). Plasmid lp17 is identical to that of lp16.9 from Barbour et al. 15 . The 11 plasmids we have described contain a total of 430 putative ORFs with an average size of 507 bp; plasmid G+C content ranges from 23.1% to 32.3%. Only 71% of plasmid DNA represents predicted coding sequences, a value significantly lower than that on the chromosome. This indicates that average intergenic distances are greater in the plasmids than in the chromosome, and that many potential ORFs contain authentic frameshifts or stops (see E29, for example), suggesting that they are decaying genes not encoding functional proteins. Of the 430 plasmid ORFs, only 70 (16%) could be identified and these include membrane proteins such as OspA-D, decorin-binding proteins, the VlsE lipoprotein recombination cas- sette, and the purine ribonucleotide biosynthetic enzymes GuaA and GuaB. We found that 100 ORFs (23%) match other hypothe- tical proteins from plasmids in this and related strains of B. burgdorferi 15,16,31 ; 10 ORFs (2.3%) match hypothetical proteins from species other than Borrelia; and 250 ORFs (58%) have no database match. We found that 47 paralogous gene families containing from 2 to 12 members account for 39% (169 ORFs) of the plasmid-encoded genes with no known biological role (Fig. 1). Paralogue families 32 and 50, typified by previously identified B. burgdorferi plasmid genes cp32 orfC and cp8.3 orf2, respectively, have some similarities to proteins involved in replication, segregation and control of copy number in other bacterial systems 16,31 . Previous studies have reported examples of plasmid gene duplication, but the extent of Table 2 Gene identification numbers are listed with the prefix BB as in Fig. 2. Each gene identified is listed in its functional role category (adapted from Riley 29 ). The percentage of similarity and a two-letter abbreviation for genus and species for the best match are also shown. An expanded version of this table with additional information is available on the World-Wide Web at http://www.tigr.org/tdb/mdb/bbdb/bbdb.htm. Abbreviations of gene names are: Ac, acetyl; BP, binding protein; biosyn, biosynthesis; cello, cellobiose; CPDase, carboxypeptidase;Dcase,decarboxylase;DHase,dehydrogenase;flgr,flagellar/flagellum; fru, fructose; GBP, glycine, betaine, L-proline; glu, glucose; Kase, kinase; mal, maltose; MC- methyl-accepting chemotaxis; MTase, methyltransferase; NAG, N-acetylglucosamine; OH, hydroxy; OP, oligopeptide; P, phosphate; PPTase, phosphotransferase; PPase, phospha- tase; prt, protein; put, putative; RDase, reductase; RG, ribose/galactose; SAM, S-adenosyl- methionine; Sase, synthetase/synthase; SP, spermidine/putrescine; ss, single-stranded; sub, subunit; Tase, transferase. Abbrevation of genus and species are: Ah, Aeromonas hydrophila; Ar, Agrobacterium radiobacter; Al, Alteromonas sp.; Ab, Anabaena sp.; An, Anacystis nidulans; At, arabidopsis thaliana; Av, Azotobacter vinelandii; Bf, Bacillus firmus; Bl, Cacillus licheniformis; Bm, Bacillus megaterium; Bs, Bacillus stearothermophilus; Bs, Bacillus subtilis; Bb, Borrelia burgdorferi; Bc, Borrelia coriaceae; Bh, Borrelia hermsii; Ba, Buchnera aphidicola; Ca, Clostridium acetobutylicum; Cl, Clostridium longisporum; Cp, Clostridium perfringens; Cg, Corynegacterium glutamicum; Cb, Coxiella burnetii; Cp, Cyanophora paradoxa; Dd, Dictyostelium discoideum; Ec, Escherichia coli; Eh, Entamoeba histolytica; Ec, Enterobacter cloacae; El, Enterococcus faecalis; Eh, Enterococcus hirae; Ha, Haemophilus aegyptius; Hi, Haemophilus influenzae; Hp, Helicobacter pylori; Hs, Homo sapiens; La, Lactobacillus acidophilus; Ll, Lactococcus lactis; Li, Leptospira interrogans serovar lai; Mj, Methanococcus jannaschii; Mb, Methanosarcina barkeri; Ml, Mycobacterium leprae; Mt, Mycobacterium tuberculosis; Mc, Mycoplasma capricolum; Mg, Mycoplasma genitalium; Mh, Mycoplasma hominis; Mh, Mycoplasma hyorhinis; Mm, Mycoplasma mycoides; Mp, Mycoplasma pneumoniae; Mx, Myxococcus xanthus; Ng, Neisseria gonorrhoeae; Nm, Neisseria meningitidis; Os, Odontella sinensis; Pt, Paramecium tetraurelia; Pa, Pediococcus acidilactici; Pf, Plasmodium falciparum; Pg, Porphyromonas gingivalis; Pv, Proteus vulgaris; Pa, Pseudomonas aeruginosa; Pm, Pseudomonas mevalonii; Pp, Pseudomonas putida; Rm, Rhizobium meliloti; Rc, Rhodobacter capsulatus; Rs, Rhodobacter sphaeroides; Rp, Rickettsia prowazekii; Sc, Saccharomyces cerevisiae; Sc, Salmonella choleraesius; St, Salmonella typhimurium; Sh, Serpulina hyodysenteriae; Sd, Shigella dysenteriae; So, Spinacia oleracea; Sc, Staphylococcus camosus; Se, Staphylococcus epidermidis; Sp, Streptococcus pyogen- es; Sc, Streptomyces coelicolor; Ss, Sulfolobus solfataricus; Syn, Synechococcus sp.; Sp, Synechocystis PCC6803; Tt, Thermoanaerobacterium thermosaccharolyticum; Tb, Ther- mophilicbacterium RT8.B4.;Ttv, Thermoproteus tenax virus; Tm, Thermotoga maritima; Tat, Thermus aquaticus thermophilus; Ta, Thermus aquaticus; Td, Treponema denticola; Tp, Treponema pallidum; Ta, Triticum aestivum; Tb, Trypanosoma brucei mitochondrion; Vc, Vibrio cholerae; Vp, Vibrio parahaemolyticus; Zm, Zymomonas mobilis. Table 1 Genome features in Borrelia burgdorferi Chromosome 910,725 bp (28.6% G+C) Coding sequences (93%) RNAs (0.7%) Intergenic sequence (6.3%) 853 coding sequences 500 (59%) with identified database match 104 (12%) match hypothetical proteins 249 (29%) with no database match ............................................................................................................................................................................. Plasmids cp9 9,386 bp (23.6% GC) cp26 26,497 bp (26.3% GC) lp17 16,828 bp (23.1% GC) lp25 24,182 bp (23.3% GC) lp28-1 26,926 bp (32.3% GC) lp28-2 29,771 bp (31.5% GC) lp28-3 28,605 bp (25.1% GC) lp28-4 27,329 bp (24.4% GC) lp36 36,834 bp (26.8% GC) lp38 38,853 bp (26.1% GC) lp54 53,590 bp (28.1% GC) Coding sequences (71%) Intergenic sequence (29%) 430 coding sequences 70 (16%) with identified database match 110 (26%) match hypothetical proteins 250 (58%) with no database match ............................................................................................................................................................................. Ribosomal RNA Chromosome coordinates 16S 444581?446118 23S 438590?441508 5S 438446?438557 23S 435334?438267 5S 435201?435312 ............................................................................................................................................................................. Stable RNA tmRNA 46973?47335 mpB 750816?751175 ............................................................................................................................................................................. Transfer RNA 34 species (8 clusters,14 single genes) ............................................................................................................................................................................. *The telomeric sequences of the nine linear plasmids assembled as part of this study were not determined; estimation of the number of missing terminal nucleotides by restriction analysis suggests that less than 1,200 bp is missing in all cases. Comparisons with previously determined sequences of lp 16.9 and one terminus of lp28-1 indicate that 25, 60 and 1,200 bp are missing, respectively. R Nature � Macmillan Publishers Ltd 1997 articles 582 NATURE | VOL 390 | 11 DECEMBER 1997 this redundancy has become even more apparent with the complete sequence of these 11 plasmids from isolate B31. Moreover, a preliminary search of 221 putative ORFs from the cp32s and lp56 indicates that at least 50% display $70% amino-acid similarity to ORFs from the other 11 plasmids presented here (data not shown). Although plasmid-encoded genes have been implicated in infectiv- ity and virulence 17?19 , the biological roles of most of these genes are not known. The significance of the large number of paralogous plasmid-encoded genes is not understood. These proteins may be expressed differentially in tick and mammalian hosts, or may undergo homologous recombination to generate antigenic varia- tion in surface proteins. This hypothesis is supported by the identification of 63 plasmid-encoded putative membrane lipopro- teins (Fig. 1). Several copies of a putative recombinase/transposase similar to IS891-like transposases were identified in the B. burgdorferi plas- mids. Linear plasmid 28-2 contains one full-length copy of this gene. Although no inverted repeats were found on either side of the transposase, there is a putative ribosome-binding site several nucleotides upstream of the apparent start codon, and a stem? loop structure (- 27 kcal mol - 1 ) 195 bp downstream of the stop codon in an area with no ORFs. This transposase might represent a functional gene important for the frequent DNA rearrangements that presumably occur in Borrelia plasmids. There are other partial or nearly complete copies of the transposase gene that contain frame-destroying mutations elsewhere in the genome: two copies on lp17, one on lp36, one on lp38, one on lp28-3, two on lp28-1, and one near the right end of the large linear chromosome. Origin of replication The replication mechanism for the linear chromosome and plas- mids in B. burgdorferi is not yet known. Replication possibly begins at the termini, as has been proposed for the poxvirus hairpin telomeres 32 , or may begin from a single origin somewhere along the length of the linear replicon. Of the genes on the linear chromosome, 66% are transcribed away from the centre of the chromosome (Fig. 1), similar to the transcriptional bias observed for the genomes of M. genitalium 21 and M. pneumoniae 33 . It has been suggested that bacterial genes are optimally transcribed in the same direction as that in which replication forks pass over them, particularly for highly transcribed genes 34,35 Given the transcriptional bias observed in B. burgdorferi, it seems likely that the origin of replication is near the centre of the chromosome. Because bacterial chromosomal replication origins are usually near dnaA 36 , it is intriguing to note that this gene (BB437) lies almost exactly at the centre of the linear B. burgdorfer- i chromosome 10,27 . A centrally initiated, bi-directional replication fork would be equidistant from the two chromosome ends, and replication would traverse the rRNA genes in the same direction as transcription. An analysis of GC skew, (G 2 C)/(G � C) calculated in 10-kilo- base (kb) windows across the chromosome, shows a clear break at the putative origin of replication. The GC-skew values are uni- formly negative from 0 to 450 kb (minus strand), and uniformly positive (plus strand) from 450 kb to the end of the chromosome (Fig. 2). Additional evidence for the location of the origin of replication comes from our discovery of an octamer, TTGTTTTT, whose skewed distribution in the plus versus the minus strand of the chromosome matches the GC skew (Fig. 2). The biological sig- nificance of this octamer has not yet been determined, although it may be analogous to the Chi site in Escherichia coli that is implicated in recBCD mediated recombination. No GC skew was observed in any of the plasmids, although the heptamer ATTTTTT displays a skewed distribution in the plus versus the minus strand of lp28-4 that changes at the approximate midpoint of the plasmid (not shown). Transcription and translation Genes encoding the three subunits (a, b, b9) of the core RNA polymerase were identified in B. burgdorferi along with j 70 and two alternative j factors, j 54 and rpoS. The role and specificity of each of these j factors in transcription regulation in B. burgdorferi are not known. The nusA, nusB and rho genes, which are involved in transcription elongation and termination, were also identified. A region of the genome with a significantly higher G � C content (43%), located between nucleotides 434,000 and 447,000, contains the rRNA operon. As previously reported, the rRNA operon in B. burgdorferi contains a 16S rRNA?Ala-tRNA?Ile-tRNA?23S rRNA?5S rRNA?23S rRNA?5S rRNA 37,38 . All of the genes are present in the same orientation, except for that encoding Ile tRNA. Four unrelated genes, encoding 3-methyladenine glycosylase, hydrolyase and two with no database match, are also present in the rRNA operon. Three of these genes are transcribed in the same direction as the rRNAs. We identified in the chromosome 31 tRNAs with specificity for all 20 amino acids (Fig. 1). These are organized into 7 clusters plus 13 single genes. All tRNA synthetases are present except glutaminyl tRNA-synthetase. A single glutamyl tRNA synthetase probably aminoacylates both tRNA Glu and tRNA Gln with glutamate followed by transamidation by Glu-tRNA amidotransferase, a heterotrimeric enzyme present in B. burgdorferi and several Gram-positive bacteria and archaea 30 . The lysyl-tRNA synthetase (LysS) in B. burgdorferi is a class I type that has no resemblance to any known bacterial or eukaryotic LysS, but is most similar to LysS from the archaea 40 . Replication, repair and recombination The complement of genes in B. burgdorferi involved in DNA replication is smaller than in E. coli, but similar to that in M. genitalium 21 . Three ORFs have been identified with high homology to four of the ten polypeptides in the E. coli DNA polymerase III: a, b and g, and t. In E. coli, the g and t proteins are produced by programmed ribosomal frameshifting. This observation suggests that DNA replication in B. burgdorferi, like that in M. genitalium, is accomplished with a restricted set of genes. B. burgdorferi has one TTGTTTTT Distribution (G-C)/(G+C) 0 200 400 600 800 910.725 0.000 0.200 -0.200 Kilobases Figure 2 Distribution of TTGTTTTT and GC skew in the B. burgdorferi chromosome. Top, distribution of the octamer TTGTTTTT. The linesinthetop panelrepresentthe locationof this octamer in the plus strand of the sequence, and those in the second panel represent the location of this oligomer in the minus strand of the sequence. Bottom, GC skew. Nature � Macmillan Publishers Ltd 1997 articles NATURE | VOL 390 | 11 DECEMBER 1997 583 type I topoisomerase (topA) and two type II topoisomerases (gyrase and topoisomerase IV) for DNA topology management and chro- mosome segregation, despite its linear chromosomal structure. This suggests that topoisomerase IV may be required for more than the separation of circular DNAs during segregation. The DNA repair mechanisms in B. burgdorferi are similar to those in M. genitalium. DNA excision repair can presumably occur by a pathway involving endonuclease III, PolI and DNA ligase. The genes for two of three DNA mismatch repair enzyme (mutS, mutL) are present. The apparent absence of mutH is consistent with the lack of GATC (dam) methylation in strain B31 (S. Casjens, unpublished). Also present are genes for the repair of ultraviolet-induced DNA damage (uvrA, uvrB, uvrC and uvrD) (Table 2). B. burgdorferi has a complete set of genes to perform homologous recombination, including recA, recBCD, sbcC, sbcD, recG, ruvAB and recJ. 39-Exonuclease activity associated with sbcB in E. coli may be encoded by exoA (exodeoxynuclease III). Although recA is present, we found no evidence for lexA, which encodes the repressor that BB586 mannose fructose glucoseglucosamine F-1-P M-6-P M-1-P Glc-6-P BB004 BB835 gluconolactone Gln-6-P BB152 BB620 glucose-?-R chitobiose chitobiose-6-P N-acetyl-Gln-6-P ribose BBB04 BBB05 BBB06 PERIPLASM CYTOPLASM glycerol BB240 N-acetyl-Gln-1-P BB207 UDP-N-acetyl-Gln UTP H + BB090 BB091 BB092 BB093 BB094 BB096 arginine citrulline ornithine + carbamoylphosphate BB841 BB842 pantothenate pantothenate BB814 lactate lactate BB604 K + BB724 K + Mg ++ BB380 Mg ++ Ca ++ BB164 Ca ++ Na + Na + ? H + BB447 BB637 BB638 H + Na + Na + BB401 BB729 phosphate phosphate BB215 BB216 BB217 BB218 oligopeptide oligopeptide ?14 proteases BBA34 BBB16 5 chemotaxis receptors 2 flagellins + 34 flagellar & motor genes chemotaxis genes 2 cheA, 2 cheB, 3 cheY, 3 cheW & 2 cheR H + H + cheB phosphorylation? Motility and Chemotaxis ? 1-4 oligo-glucose, maltose BB166 EII BB408 BB629 8 murien synthesis genes 9 cell wall associated genes BB002 BB151 F-1,6-dP DHP G-3-P glycerol-3-Pglycerol 1,3-BPG 3-PG 2-PG PEP pyruvate lactate BB730 BB020 BB727 BB445 BB241 BB057 BB056 BB658 BB337 BB348 BB087 BB630 BB222 BB636 NADH NAD + ATP ADP NADH NAD + PP i P i BB243 BB368 NADHNAD + BB055 EI ATP ADP BBB29 BB559 BB645 F-6-P BB407 A B C BB677 BB678 BB679 BB657BB561 6-P-gluconate ribulose-5-P ribose-5-P ATP BB544 AMP NADHNAD + H + ATP ADP acetate ATP acetate-P CoA BB622 BB589 BB327 BB037 phosphatidic acid ACP-R BB704 BB137 BB593 CTP PP i CMP-phosphatidic acid NH 2 C-SH BB362 BB469 phosphatidyl glycerol membrane sec protein excretion BB030 BB031 BB154 BB263 phosphatidyl glycerol CMP G-3-P P i acetyl-CoA fatty acids ADP BB686 aceto-acetate HMG-CoA acetyl-CoA BB683 mevalonate BB685 NADH NAD + CoA BB688 ATP ADP BB687 activated isoprene 5-phosphomevalonate ATP ADP ATP ADP BB395 BB498 BB652 BB653 C-S-CH 2 -CH-CH 2 -O-C-R 2 O -O-C-R 1 O == NH 2 NH O -O-C-R 3 = C-S-CH 2 -CH-CH 2 -O-C-R 2 O -O-C-R 1 O == NH 2 C-S-CH 2 -CH-CH 2 -O-C-R 2 O -O-C-R 1 O == ~ 105 V 0 V 1 ATPase BB144 BB145 BB146 A B C spermidine putrescine BB328 BB329 BB330 BB332 BB333 BB334 BB335 BB746 BB747 A B C A B C amino acids dnaA (BB437), gidA (BB178), gidB (BB177)Ori initiation DNA synthesis dnaG (BB710), priA (BB014), dnaB (BB111), RNase H (BB046) dnaE (BB579), dnaN (BB438), dnaX (BB461), ssb (BB114), ligase (BB552) DNA topology gyrA,B (BB435/BB436), topA (BB828), parE,C (BB036/BB035) spoOJ (BB434), helicase (BB607/BB827/BBG34) Others DNA Recombination recB,C,D (BB634/BB633/BB632), recJ (BB254) recA (BB131) ruvA,B (BB023/BB022), recG (BB581) DNA Repair uvrA,B,C,D (BB837/BB836/BB457/BB344) polI (BB548) mutS (BB797/BB098), mutL (BB211) mfd (BB623) ung (BB053) mag (BB422) DNA Replication RNA Synthesis rpoA,B,C (BB502/BB389/BB388) sigma 70 (BB712) sigma 54 (BB450) sigma S (BB771) greA (BB132) nusA,B,G (BB800/BB394/BB107) rho (BB230) Mature RNAs RNaseIII (BB705) pnpA (BB805) RNaseP (BB441) papS (BB706) RNA polymerase sigma factors elongation factors termination ~100 protein encoding genes 2 23S & 5S rRNA genes 1 16S rRNA gene 1 10S rRNA gene 34 tRNA genes groEL (BB649), groES (BB741) dnaK (BB518/BB264), dnaJ (BB655/BB517) grpE (BB519), htpG (BB560) chaperonins Translation folded proteins Nicotinic acid adenine dinucleotide glutamine (or NH 3 ) glutamic acid NAD + AMP + PP i ATP BB522 NADH BB728 H 2 O O 2 O 2 . - BB153 H 2 O 2 BB417 BB463 BB618 BB128 BB819 BB571 BB015 rUrXMP rIMP BBB18 BB015 BB463BB463 BB463 PRPP adenine BB777 rAMP PP i rADP rATP rCMP rCDP rCTP rUMP rUDP rUTP rGMP rGDP rGTP BBB17 rC porin BBA74 BB119 BB721 BB639 BB640 BB641 BB642 BB575 BB140 BB141 BBI26 drug efflux BB116 sbcC,D (BB830/BB829), exoIII (BB534) endonucleases (BB411, BB745) K + K + tRNA loading ribosomes factors rRNAs, tRNAs Cell Division ftsA (BB300) ftsH (BB789) ftsJ (BB313) ftsK (BB257) ftsQ (BB301) ftsW (BB302) ftsZ (BB299) minD (BB361) glycine serine BB601 tetrahydrofolate N 5 , N 10 -methylene tetrahydrofolate N 5 , N 10 -methenyl tetrahydrofolate BB026 ribose PTS transport BB558 BB557 BB448 HPr EI BB239BB239 BB791 BB618 BB417 BB128 BB819 BB015BB791 BB793 BB463 BB463 BB463 BB463 dAMP dADP dATP dCMP dCDP dCTP dTMP dTDP dTTP dGMP dGDP dGTP dUMP dU dCdTdG dA BB258 ACP EII EII phosphate & leader peptidases lipoproteins insertion mevalonate 5-pyrophospho mevalonate 3-phospho-5-pyrophospho glutamic acid glycine proline spermidine putrescine glucosamine galactose N-acetyl- glutamic acid glycine proline acids amino wall cell Protein Protein Protein Protein Figure 3 Solute transport and metabolic pathways in B. burgdorferi. A schematic diagram of a B. burgdorferi cell providing an integrated view of the transporters and the main components of the metabolism of this organism, as deduced from the genes identified in the genome. The ORF numbers correspond to those listed in Table 2 (red indicates chromosomal and blue indicates plasmid ORFs). Presumed transporter specificity is indicated. Yellow circles indicate: places where particular uncertainties exist as to the substrate specificity, subcellular location or direction of catalysis: or expected activities that were not found. Nature � Macmillan Publishers Ltd 1997 articles 584 NATURE | VOL 390 | 11 DECEMBER 1997 regulates SOS genes in E. coli. No genes encoding DNA restriction or modification enzymes are present. Biosynthetic pathways The small genome size of B. burgdorferi is associated with an apparent absence of genes for the synthesis of amino acids, fatty acids, enzyme cofactors, and nucleotides, similar to that observed with M. genitalium 21 (Fig. 3, Table 2). The lack of biosynthetic pathways explains why growth of B. burgdorferi in vitro requires serum-supplemented mammalian tissue-culture medium. This is also consistent with previous biochemical data indicating that Borrelia lack the ability to elongate long-chain fatty acids, such that the fatty-acid composition of Borrelia cells reflects that present in the growth medium 6 . Transport The linear chromosome of B. burgdorferi contains 46 ORFs and the plasmids contain 6 ORFs that encode transport and binding proteins (Fig. 3, Table 2). These gene products contribute to 16 distinct membrane transporters for amino acids, carbohydrates, anions and cations. The distribution of transporters between the four categories of functions in this section is similar to that observed in other heterotrophs (such as Haemophilus influenzae, M. genita- lium and H. pylori), with most being dedicated to the import of organic compounds. There are marked similarities between the transport capacity of B. burgdorferi and M. genitalium. Both genomes have a limited number of recognizable transporters, so it is not clear how they can sustain diverse physiological reactions. Several of the identified transporters in both genomes exhibit broad substrate specificity, exemplified by the oligopeptide ABC transporter (opp operon) or the glycine, betaine, L-proline transport system (proVWX). There- fore, these organisms probably compensate for their restricted coding potential by producing proteins that can import a wide variety of solutes. This is important because B. burgdorferi is unable to synthesize any amino acids de novo. We were unable to identify any transport systems for nucleosides, nucleotides, NAD/NADH or fatty acids, although they are likely to be present. Glucose, fructose, maltose and disaccharides seem to be acquired by the phosphoenolpyruvate:phosphotransferase system (PTS). The two nonspecific components, enzyme 1 (ptsl) and Hpr (ptsH), are associated in one operon with an apparently glucose-specific, phosphohistidine-sugar phosphotransferase enzyme IIA (crr). Separate from this operon are four permeases (enzyme IIBC), fruA in two copies (fructose), ptsG (glucose) and malX (glucose/ maltose) (Fig. 3, Table 2). The fructose-specific enzyme IIA is induced in the ORF with IIBC (fruA), as has been observed in M. genitalium 41 . Ribose may be imported by an ATP-binding cassette transporter (rbsAC). The rbsAC genes are transcribed in an operon with a methyl-accepting chemotaxis protein that may respond to b- galactosides, suggesting that movement of the organisms towards sugars may be coupled to the transport process. Energy metabolism The limited metabolic capacity of B. burgdorferi is similar to that found in M. genitalium (Fig. 3, Table 2). Genes encoding all of the enzymes of the glycolytic pathway were identified. Analysis of the metabolic pathway suggests that B. burgdorferi uses glucose as a primary energy source, although other carbohydrates, including glycerol, glucosamine, fructose and maltose, may be used in glycolysis. Pyruvate produced by glycolysis is converted to lactate, consistent with the microaerophilic nature of B. burgdorferi. Gen- eration of reducing power occurs through the oxidative branch of the pentose pathway. None of the genes encoding proteins of the tricarboxylic acid cycle or oxidative phosphorylation were identi- fied. The similarity in metabolic strategies of two distantly related, obligate parasites, M. genitalium and B. burgdorferi, suggests con- vergent evolutionary gene loss from more metabolically competent, distant progenitors. Addition of N-acetylglucosamine (NAG) to culture medium is required for growth of B. burgdorferi 6 . NAG is incorporated into the cell wall, and may also serve as an energy source. The cp26 plasmid encodes a PTS cellobiose transporter homologue that could have specificity for the structurally similar compound chitobiose (di-N- acetyl-D-glucosamine). A gene product on the chromosome with sequence similarity to chitobiase (BB2) may convert chitobiose to NAG. B. burgdorferi can metabolize NAG to fructose-6-phosphate, which then can enter the glycolytic cycle through the action of N- acetylglucosamine-6-phosphate deacetylase and glucosamine-6- phosphate isomerase. NAG is the primary constituent of chitin, which makes up the tick cuticle 6 , and may be a source of carbo- hydrate for B. burgdorferi when it is associated with its tick host. The parallels between B. burgdorferi and M. genitalium appear to extend to other aspects of their metabolism. Both organisms lack a respiratory electron transport chain, so ATP production must be accomplished by substrate-level phosphorylation. Consequently, membrane potential is established by the reverse reaction of the V 1 V 0 -type ATP synthase, here functioning as an ATPase to expel protons from the cytoplasm (Fig. 3, Table 2). The ATP synthase genes in B. burgdorferi appear to be transcribed as part of a seven- gene operon. They are not typical of those usually found in eubacteria, more closely resembling the eukaryotic vacuolar (V- type) and archaeal (A-type) H + -translocating ATPases 42 , both in size TATTTATTATCTTTTAGTATATATATCTCTCG-3' ATAAATAATAGAAAATCATATATATAGAGAGC- AATATATAATCTAATAGTATACAAAAGATTCA-3' TTATATATTAGATTATCATATGTTTTCTAAGT- AAATATAATTTAATAGTATAAAAAACTGTTT-3' TTTATATTAAATTATCATATTTTTTGACAAA- TAAATATAATTTAATAGTATAAAAAAAATTAA-3' ATTTATATTAAATTATCATATTTTTTTTAATT- ? 3 1 2 8 ? ? ? ATATAATTTGATATTAGTACAAATCCCCTTGC-3' TATATTAAACTATAATCATGTTTAGGGGAACG- ATATAATATTTATTTAGTACAAAGTTCAATTT-3' TATATTATAAATAAATCATGTTTCAAGTTAAA- ATATAATTTTTTATTAGTATAGAGTATTTTGA-3' TATATTAAAAAATAATCATATCTCATAAAACT- ATATAATTTTTAATTAGTATAGAATATGTTAA-3' TATATTAAAAATTAATCATATCTTATACAATT- 5 6 7 4 ? ? Figure 4 Telomere nucleotide sequences from Borrelia species. Nucleotide sequencesareshownforknown Borreliatelomeresasindicated:1,B.burgdorferi Sh-2-82 chromosome left end; 2, B. burgdorferi B31 chromosome left end; 3, B. afzelii R-IP3 chromosome right end; 4, B. burgdorferi B31 chromosome right end; 5, B. burgdorferi B31 plasmid Ip17 left end; 6, B. burgdorferi B31 plasmid Ip17 right end; 7, B. hermisii plasmids bp7E and pb21E right ends; 8, B. burgdorferi B31 plasmid Ip28-1 right end. In each case the telomere is at the left. Question marks (?) indicate locations where S1 nuclease was used to open terminal hairpins during the sequence determinations.Stippled areas highlight regions that appear to have been most highly conserved among these telomeres; no strong sequence conservation has been found near the right of the terminal 26 bp among the different sequences listed, except between the chromosomal left ends from strains B31 and Sh-2-82 (see text). The telomeric sequences of the strain B31 chromosome were determined in this report; the others are from references 14, 28, 30, 45, 46. Nature � Macmillan Publishers Ltd 1997 articles NATURE | VOL 390 | 11 DECEMBER 1997 585 and sequence similarity, than the bacterial F 1 F 0 ATPases. Genome analysis of Treponema pallidum, the pathogenic spirochaete that causes syphilis, has also revealed the presence of a V 1 V 0 -type ATP synthase (C. M. F. et al., manuscript in preparation), suggesting that this may be a feature of spirochaetes. Regulatory systems Although the expression of Borrelia genes varies according to the current host species, temperature, host body location and other local factors, control of gene expression appears to differ from more well studied eubacteria. A typical set of homologues of heat-shock response genes is present (groES, groEL, grpE, dnaJ, hslU, hslV, dnaK and htpG), and B. burgdorferi is known to have such a response; however, it lacks the j-32 that controls their transcription in E. coli. Only a few homologues to other eubacterial regulatory proteins are present, including only two response-regulator two-component systems. Motility and chemotaxis Like other spirochaetes, B. burgdorferi has periplasmic flagella that are inserted at each end of the cell and extend towards the middle of the cell body. The unique flagella allow the organism to move through viscous solutions, an ability that is presumed to be important in its migration to distant tissues following deposition in the skin layers 43 . Proteins involved in motility and chemotaxis are encoded by 54 genes, more than 6% of the B. burgdorferi chromo- some, most of which are arranged in eight operons containing between 2 and 25 genes. B. burgdorferi contains several copies of the chemotaxis genes (cheR, cheW, cheA, cheY and cheB) downstream of the methyl- accepting chemotaxis proteins. Other eubacteria also have duplica- tions of some che genes, but those genes in B. burgdorferi are the most redundant set yet found. B. burgdorferi lacks recognizable virulence factors; thus, its ability to migrate to distant sites in the tick and mammalian host is probably dependent on a robust chemotaxis response. Multiple chemotaxis genes may provide redundancy in this system in order to meet such challenges or, alternatively, these genes may be differentially expressed under varied physiological conditions. Another speculative possibility is that the flagellar motors at the two ends of the B. burgdorferi cell are different and require different che systems. In support of this idea is the observation that one of the motor switch genes, fliG, is also present in two copies. Membrane protein analysis Much of the previous work on B. burgdorferi has focused on outer- surface membrane genes because of their potential importance in bacterial detection and vaccination. Nearly all Borrelia membrane proteins have been found to be typical bacterial lipoproteins. A search of B. burgdorferi ORFs for a consensus lipobox in the first 30 amino acids identified 105 putative lipoproteins, representing more than 8% of coding sequences. This contrasts with a total of only 20 putative lipoproteins in the 1.67-million base pair H. pylori genome (1.3% of coding sequences) 23 . The periplasmic binding proteins involved in transport of amino acids/peptides and phosphate in B. burgdorferi are candidate lipoproteins, suggesting that they may be anchored to the outer surface of the cytoplasmic membrane as in Gram-positive bacteria, rather than localized in the periplasmic space. In better-characterized eubacteria, prolipoprotein diacylglycerol transferase (lgt), prolipoprotein signal peptidase (lsp), and apoli- poprotein:phospholipid N-acyl transferase (lnt) are required for post-translational processing and addition of lipids to the amino- terminal cysteine. Genes for the first two of the enzymes (lgt and lsp) are present in the B. burgdorferi genome, but the gene for lnt was not identified, although biochemical evidence argues for all three activities in B. burgdorferi 44 . The sequence similarity of an lnt homologue in B. burgdorferi may be too low to be identified using our search methods, or its activity may be present in a new enzyme. In E. coli the Sec protein export system moves lipoproteins through the inner membrane, and Borrelia carries a complete set of these protein-secretion gene homologues (secA/D/E/F/Y and tth; only the non-essential secB is missing). Analysis of telomeres The two chromosomal telomeres of strain B31 have similar 26-bp inverted terminal sequences (Fig. 4). We found no other similarity between the two ends, and these 26-bp sequences are very similar to the previously characterized Borrelia telomeres. Terminal restriction fragments from both B31 chromosomal termini were shown to exhibit snapback kinetics (data not shown), strongly indicating that both terminate in covalently closed hairpins, like previously char- acterized Borrelia telomeres 28,45,46 . The left chromosomal telomere of strain B31 is identical to the previously characterized left telomere of strain Sh-2-82 (ref. 28), except for a 31 bp insertion in B31 26 bp from the end. The right- most 7,454 bp contains surprisingly few ORFs, given the ORF density elsewhere on the chromosome. The function of this region is unknown, but it contains several unusual features. The right terminal 900 bp contains considerable homology to the left ends of lp17 and lp28-3. The region between 3,600 bp and 8,000 bp from the right end also contains several areas with similarity to plasmid sequences, including a portion of the transposase-like gene approximately 4,500 bp from the right end. The spacing between the two conserved motifs (ATATAAT and TAGTATA) in the right 26-bp terminal repeat is the same as most previously known plasmid telomeres but different from the previously known chromosomal telomeres. These findings support the idea that the right end of the Borrelia chromosome has historically exchanged telomeres with the linear plasmids 28 . Conclusions The B. burgdorferi genome sequence will provide a new starting point for the study of the pathogenesis, prevention and treatment of Lyme disease. With the exception of a small number of putative virulence genes (haemolysins and drug-efflux proteins), this organ- ism contains few, if any, recognizable genes involved in virulence or host?parasite interactions, suggesting that B. burgdorferi differs from better-studied eubacteria in this regard. It will be interesting to determine the role of the multi-copy plasmid-encoded genes, as previous work has implicated plasmid genes in infectivity and virulence. The completion of the genome sequence from a second spirochaete, Treponema pallidum (C.M.F. et al., manuscript in preparation) will allow for the identification of genes specific to each species and to this bacterial phylum, and will provide further insight into prokaryotic diversity. M . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods Cell lines. A portion of a low-passage subculture of the original Lyme-disease spirochaete tick isolate 4 was obtained from A. Barbour. The type strain of B. burgdorferi (ATCC 35210) 3 , B31, was derived from this isolate by limiting dilution cloning 5 . Cells were grown in Barbour?Stoenner?Kelly medium II (BSKII) 6 , omitting the additions of antibiotics and gelatin, in tightly closed containers at 33?34 8C. Cells were subcultured three or fewer times in vitro between successive rounds of infection in C3H/HeJ mice to minimize loss of infectivity and plasmid content 17,18 . After four successive transfers of infection in mice, a primary culture of B31, established from infected ear tissue, was expanded to 2.5 l by four successive subcultures. All available evidence indicates that the B31 line used for preparation of genomic DNA was probably clonal, as genetic heterogeneity was undetectable by several criteria including macro- restriction analysis (S. Casjens, unpublished data) and plasmid analysis of clonal derivatives of the B31 line 13 . Sequencing. The B. burgdorferi genome was sequenced by a whole-genome random sequencing method previously applied to other microbial genomes 20?24 . Nature � Macmillan Publishers Ltd 1997 articles 586 NATURE | VOL 390 | 11 DECEMBER 1997 An approximately 7.5-fold genome coverage was achieved by generating 19,078 sequences from a small insert plasmid library with an average edited length of 505 bases. The ends of 69 large insert lambda clones were sequenced to obtain a genome scaffold; 50% of the genome was covered by at least one lambda clone. Sequences were assembled using TIGR Assembler as described 20?24 , resulting in a total of 524 assemblies containing at least two sequences, which were clustered into 85 groups based on linking information from forward and reverse sequence reads. All Borrelia sequences that had been mapped were searched against the assemblies in an attempt to delineate which were derived from the various elements of the B. burgdorferi genome. Some contigs were also located on the existing physical map by Southern analysis. Sequence and physical gaps for the chromosome were closed as described 20?24 . At the completion of the project, less than 3% of the chromosome had single-fold coverage. The linear chromosome of B. burgdorferi has covalently closed hairpin structures at its termini that are similar to those reported for linear plasmids in this organism 11 . The telomeric sequences (106 and 72 bp, respectively, from the left and right ends) were obtained after nicking the terminal loop with S1 nuclease and amplifying terminal sequences by ligation-mediated polymerase chain reaction (PCR) as described 28 . The unknown terminal sequence was determined in both directions on four independent plasmid clones of the amplified DNA from each telomere. A minimum amount of S1 nuclease was used and, because of their sequence similarity to other Borrelia telomeres, it is likely that few, if any, nucleotides were lost from the B31 chromosomal telomeres in this process. Identification of ORFs. Coding regions (ORFs) were identified using compositional analysis using an interpolated Markov model based on variable-length oligomers 47 . ORFs of .600 bp were used to train the Markov model, as well as B. burgdorferi ORFs from GenBank. Once trained, the model was applied to the complete B. burgdorferi genome sequence and identified 953 candidate ORfs. ORFs that overlapped were visually inspected, and in some cases removed. Non-overlapping ORFs that were found between predicted coding regions and .30 amino acids in length were retained and included in the final annotation. All putative ORFs were searched against a non-redundant amino-acid database as described 20?24 . ORFs were also analysed using 527 hidden Markov models constructed for several conserved protein families (PFAM v2.0) using HMMER 48 . Families of paralogous genes were constructed by pairwise searches of proteins using FASTA. Matches that spanned at least 60% of the smaller of the protein pair were retained and visually inspected. A total of 94 paralogous gene families containing 293 genes were identified (Fig. 1). Identification of membrane-spanning domains (MSDs). TopPred 49 was used to identify potential MSDs in proteins. A total of 526 proteins containing at least one putative MSD were identified, of which 183 were predicted to have more than one MSD. The presence of signal peptides and the probable position of a cleavage site in secreted proteins were detected using Signal-P as described 23 ; 189 proteins were predicted to have a signal peptide. Lipoproteins were identified by scanning for a lipobox in the first 30 amino acids of every protein. 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USA (in the press). 41. Reizer, J., Paulsen, I. T., Reizer, A., Titgemeyer, F. & Saier, M. H. Jr Novel phosphotransferase system genes revealed by bacterial genome analysis: The complete complement of pts genes in Mycoplasma genitalium. Microb. Comp. Genom. 1, 151?164 (1996). 42. Takase, K. et al. Sequencing and characterization of the ntp gene gluster for vacuolar-type Na+- translocating ATPase of Enterococcurs hirae. J. Biol. Chem. 269, 11037?11044 (1994). 43. Sadziene, A., Rosa, P. A., Thompson, P. A., Hogan, D. M. & Barbour, A. G. Antibody-resistant mutants of Borrelia burgdorferi: in vitro selection and characterization. J. Exp. Med. 176, 799?809 (1992). 44. Brandt, M. E., Riley, B. S., Radolf, J. D. & Norgard, M. V. Immunogenic integral membrane proteins of Borrelia burgdorferi are lipoproteins. Infect. Immun. 58, 983?991 (1990). 45. Hinnebusch, J., Bergstrom, S. & Barbour, A. Cloning and sequence analysis of linear plasmid telomeres of the bacterium Borrelia burgdorferi. Mol. Microbiol. 4, 811?820 (1990). 46. Kitten, T. & Barbour, A. Juxtaposition of expressed variable antigen genes with a conserved telomere in the bacterium Borrelia hermsii. Proc. Natl Acad. Sci. USA 87, 6077?6081 (1990). 47. Salzberg, S., Delcher, A., Kasif, S. & White, O. Microbial gene identification using interpolated Markov models. Nucleic Acids Res. (in the press). 48. Sonnhammer, E. L. L., Eddy, S. R. & Durbin, R. Pfam: a comprehensive database of protein families based on seed alignments. Proteins 28, 405?420 (1997). 49. Claros, M. G. & von Heijne, G. TopPred II: an improved software for membrane proteins structure predictions. Comput. Appl. Biosci. 10, 685?686 (1994). Acknowledgements. We thank A. G. Barbour for isolation of the Borrelia burgdorferi strain; A. Barbour, P. Rosa, K. Tilly, J. Riberio, B. Stevenson and D. Soll for discussions; N. K. Patel for technical assistance; M. Heaney, J. Scott and A. Saeed for software and database support; and V. Sapiro, B. Vincent and D. Maas for computer system support. This work was supported by a grant to J.C.V. and C.M.F. from the G. Harold and Leila Y. Mathers Charitable Foundation. Correspondence and requests for materials should be sent to C.M.F. (e-mail: gbb@tigr.org). The annoted genome sequence and gene family alignments are available on the World-Wide Web at http:// www.tigr.org/tdb/mdb/bbdb/bbdb.html. Sequences have been deposited with GenBank under the following accession numbers: AE00783 (chromosome); AE00784 (lp28-3); AE000785 (lp25); AE00786 (lp28-2); AE00787 (lp38); AE00788 (lp36); AE00789 (lp28-4); AE00790 (lp54); AE00791 (cp9); AE00792 (cp26); AE00793 (lp17); and AE00794 (lp28-1). Nature � Macmillan Publishers Ltd 1997 LP B27 B28 B29 B26 16 glu 11 94 12 94 12 37 aa 49 32 50 51 cellobiose 10 E32 E31 LP 83 60 49 57 50 32 49 44 26 1 F32 LP 57 50 32 49 66 85 68 64 65 50 32 70 71 72 7383 79 77 80 88 G34 G33 G32 G31 G30 G29 G28 G27 G26 G25 LP 88 80 46 50 51 86 86 49 32 50 57 82 12 H41 H40 H39 H38 H37 H36 H35 H34 H33 H32 LP 48 82 12 51 61 60 49 32 50 62 81 80 1 83 79 77 76 I43 I42 LP I41 I40 I39 I38 I37 I36 I35 55 52 82 49 54 54 93 54 93 60 48 60 60 60 10 49 32 50 57 60 60 59 26 84 79 K54 K53LP K52 LP K51 K50 K49 LP K48 K47 LP K46 K45 K44 K43 K42 K41 K40 K39 K38 K37 K36 K35 K34 55 52 44 75 69 75 69 75 75 73 72 71 70 58 59 66 68 64 49 62 50 32 61 60 40 59 1 59 1 1 1 12 65 1 J52 LP J51 J50 J49 J48 J47 J46 J45 J44 J43 J42 J41 J40 J39 J38 J37 J36 LP J35 J34 LP J33 J32 J31 J30 J29 59 91 90 54 92 92 59 91 90 4 ? 62 50 32 49 81 58 12 60 60 A76 A75 A74 A73 LP A72 A71 A70 A69 A68 A67 A66 LP A65 LP A64 LP A63 A62LP 87 54 54 54 54 87 87 87 A61 A60 LP A59LP A58 A57 LP A56 A55 A54 A53 A52 A51 A50 A49 A48 A47 A46 A45 A44 A43 A42 A41 A40 A39 A38 A37 A36 LP A35 LP aa 37 74 74 49 32 50 57 53 53 44 48 C12 C11 C10 LP C09 LP C08 C07 C06 C05 C04 C03 C02 C01 63 63 49 50 57 D25 D24LP D23 D22 D21 D20 D19 D18 D17 D16 D15 D14 D13 D12 D11 D10 LP D09 D08 D07 D06 D05 D04 D03 D02 D01 85 51 57 84 83 79 77 76 lp54lp38lp36lp28-4lp28-3lp28-2lp28-1lp25cp26 lp17cp9 A01 A02 A03 LP A04 LP A05 A06 LP A07 A08 A09 A10 A11 A12 A13 LP A14 LP A15 LP A16 A17 A18 A19 A20 A21 A22 A23 LP A24 LP A25 A26 A27 A28 A29 A30 A31 A32 LP A33 A34 LP J01 J02 J03 J04 J05 J06 J07 J08 LP J09 J10 J11 J12 J14 J13 J15 J16 J17 J18 J19 J20 J21 J22 J23 J24 J25 J26 J27 J28 K26 K27 K28 K29 K30 K31 K32 K33 K01 K02 K03 LP K04 K05 K06 LP K07 K08 K09 K11 K10 LP K12 K13 K14 K15 K16 K17 K18 LP K19 K20 K21 K22 K23 K24 K25 I01 I02 I03 I04I05 I06 I07 I08 I09 I10 I11 I12 I13 LP I14 I15 LP I16 I17 I18 I19 I20 I21 I22 I23 I24 I25 I26 I27 LP I28 LP I29 I30 I31 LP I32 I33 LP I34 LP H01 H02 H03 H04 H05 H06 H07 H08 H09 H10 H11 H12 H13 H14H15 H16 H17 LP H18 H19 H20 H21H22 H23 H24 H25 H26 H27 H28 H29 H30 H31 G01 LP G02 G03 G04 G05 G06 G07 G08 G09 G10 G11 G12 G13 G15 G14 G16 G17 G18 G19 G20 G21 G22 G23 G24 F01 F02 F03 F04 F05 F06 F07 F08 F09 F10 F11 F12 F13 F14 F15 F16 F17 F18 F19 LP F20 F21 F22 F23 F24 F25 F26 F27 F28 F29 F30 F31 F32 E01 E02 E03 E04 E05 LP E06 E07 LP E08 LP E09 E10 E11 E12E13 E14 E15 E16 E17 E18 E19 E20 E21 E22 E23 E24 E26E25 E27 LP E28 E29 E30 B01 B02 B03 B05 B06 B07 LP B08 LP B09 B10 B11 B12 B13 LP B14 B15 LP B16 B17 B18 LP B19 B20 B21 B22 B23 B24 B25 cellobiose cellobiose B04 93 16S Cellular processesCell en v elope 136 Amino acid biosynthesis T ranscription 258 680 5s rRNA 431 604 726 10 Pi 119 F e+++ 9 94 23S T ranspor t/binding proteins Regulator y functions Energy metabolism F atty acid/Phospholipid metabolism Purines, p yrimidines, nucleosides and n ucleotides Replication 8 5S 43 44 4 Central intermediar y metabolism Biosynthesis of cof actors, prosthetic g roups, carriers P,gly-bet Other categories UnknownConser v ed h ypothetical 4 16S 1 23s rRNA Pi 2 1 16s rRNA 1 1 6 aa 42 Na+/Ca+ tRNA 1 4 19 aa 2 4 2 2 1 35 2 fru 9 E 1 1 12 35 36 34 9 8 6 45 41 pan 12 25 56 13 6 6 67 T ranslation 7 78 78 89 2 8 3 4 Pi 41 Pi ? 6 aa 5 aa 4 ? 4 36 7 34 E,D 36 36 Mg2+ 26 23 16 10 6 7 mal 11 6 ? 7 ? 7 6 K+ 12 8 11 9 6 18 1 kb 46 1 39 39 89 8 10 11 4 aa 4 aa 1 13 13 13 rib 8 rib 5 8 4 rib 67 14 15 4 ? 6 16 glu 10 11 4 s/p s/p 43 8 6 6 s/p 1 s/p 17 H+/Na+ 12 aa 6 37 17 H+/Na+ 10 18 7 38 12 8 40 aa 4 19 fru 10 20 21 37 aa 37 22 3 18 lac 8 7 42 glyc 10 13 lac 13 24 24 47 6 ? 9 8 25 8 7 6 1 9 26 56 10 56 10 20 7 ? 27 28 9 47 6 1 glu glu 38 2 34 12 1 glu 14 11 6 9 15 27 22 33 30 8 56 10 4 ? 31 29 29 glu H+/Na+ 48 11 23 6 39 45 8 6 7 ? 11 30 31 32 32 28 33 9 2 8 21 7 1 2 LP 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 LP 28 29 30 31 32 33 34 35 36 37 LP 38 39 40 41 42 43 44 45 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 LP 70 LP 71 72 73 74 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551 552 LP 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 LP 606 607 608 609 610 611 612 613 614 615 616 617 618 619 LP 620 LP 621 622 623 624 625 626 627 LP 628 629 630 631 632 633 634 635 636 637 LP 638 639 640 641 642 643 LP 644 645 646 647 648 649 650 651 LP 652 653 654 655 656 657 658 659 660 661 662 663 LP 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 LP 687 688 LP 689 690 691 692 693 694 695 LP 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 LP 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 LP 758 759 LP 760 761 762 763 764 765 766 767 768 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 LP 785 786 787 788 789 790 791 792 794 793 795 796 797 798 799 800 801 802 803 804 805 LP 806 807 808 809 809 810 811 812 LP 813 814 LP 815 816 817 818 819 820 821 822 LP 823 824 825 826 827 LP 828 829 830 831 LP 832 833 834 835 836 837 838 839 LP 840 841 841 842 843 LP 844 845 847846 848 849 850 851 852 853 45,000 nt 90,000 135,000 180,000 315,000 360,000 405,000 450,000 495,000 540,000 675,000 720,000 585,000 810,000 855,000 900,000 P,gly-bet P,gly-bet 5S rrlA 23S rrlA 5S rrlB 23S rrlB 765,000 Signal peptide Lipoprotein LP T ranspor ter GES region P aralogous gene f amily A uthentic F rame Shift Nature � Macmillan Publishers Ltd 1997 Nature � Macmillan Publishers Ltd 1997 lp28-2 BBG08 stage 0 sporulation prt J (spoOJ) {Bb} 66 Cell killing BB143 a -hemolysin (hlyA) {Ah} 62 BB117 hemolysin III (yplQ) {Bs} 61 BB506 hemolysin (tlyA) {Sh} 59 BB059 hemolysin (tlyC) {Sh} 65 BB202 hemolysin, put {Syn} 54 Chaperones BB741 chaperonin (groES) {Pg} 77 BB602 chaperonin, put {Cb} 72 BB519 grpE prt (grpE) {Bb} 100 BB295 heat shock prt (hslU) {Bb} 100 BB296 heat shock prt (hslV) {Bb} 100 BB649 heat shock prt (groEL) {Bb} 100 BB517 heat shock prt (dnaJ-1) {Bb} 100 BB655 heat shock prt (dnaJ-2) {Ca} 59 BB264 heat shock prt 70 (dnaK-1) {Bb} 61 BB518 heat shock prt 70 (dnaK-2) {Bb} 100 BB560 heat shock prt 90 (htpG) {Bb} 100 Detoxification BB153 superoxide dismutase (sodA) {Hi} 68 BB690 neutrophil activating prt (napA) {Hi} 57 BB179 thiophene and furan oxidation prt (thdF) {Bb} 100 Protein and peptide secretion BB154 preprt translocase sub (secA) {Bb} 100 BB395 preprt translocase sub (secE) {Bl} 62 BB498 preprt translocase sub (secY) {Sc} 64 BB362 prolipoprt diacylglyceryl Tase (lgt) {Ec} 56 BB652 prt-export membrane prt (secD) {Ec} 63 BB653 prt-export membrane prt (secF) {Hi} 63 BB030 signal peptidase I (lepB-1) {Bs} 51 BB031 signal peptidase I (lepB-2) {Syn} 57 BB263 signal peptidase I (lepB-3) {St} 57 BB469 signal peptidase II (lsp) {Sc} 60 BB694 signal recognition particle prt (ffh) {Bs} 70 BB610 trigger factor (tig) {Hi} 50 Transformation BB591 competence locus E, put {Bs} 54 BB798 competence prt F, put {Hi} 52 Central intermediary metabolism General BB241 glycerol kinase (glpK) {Ec} 74 BB243 glycerol-3-P DHase, anaerobic (glpA) {Hi} 52 BB376 SAM Sase (metK) {Bs} 72 Amino sugars BB152 glucosamine-6-P isomerase (nagB) {Hi} 79 BB151 N-Acglucosamine-6-P deAcase (nagA) {Hi} 54 Degradation of polysaccharides BB620 b -glucosidase, put {Syn} 58 BB002 b -N-Achexosaminidase, put {As} 54 Phosphorus compounds BB533 phnP prt (phnP) {Ec} 48 Polysaccharides - (cytoplasmic) BB166 4-a ?glucanoTase (malQ) {Syn} 55 BB004 phosphoglucomutase (femD) {Mj} 52 BB835 phosphomannomutase (cpsG) {Hi} 57 Energy metabolism Aerobic BB728 NADH oxidase, water-forming (nox) {Sh} 59 Amino acids and amines BB841 arginine deiminase (arcA) {Cp} 75 BB842 ornithine carbamoylTase (arcB) {Ng} 74 Anaerobic BB016 glpE prt (glpE) {Hi} 53 BB087 L-lactate DHase (ldh) {Bs} 72 ATP-proton motive force interconversion BB094 V-type ATPase, sub A (atpA) {Mb} 64 BB093 V-type ATPase, sub B (atpB) {Mb} 62 BB092 V-type ATPase, sub D (atpD) {Mj} 51 BB096 V-type ATPase, sub E (atpE) {Mj} 54 BB091 V-type ATPase, sub I (atpI) {Eh} 53 BB090 V-type ATPase, sub K (atpK) {Mj} 54 Electron transport BB061 thioredoxin (trxA) {Ec} 59 BB515 thioredoxin RDase (trxB) {Bb} 99 Fermentation BB622 acetate kinase (ackA) {Ec} 63 BB589 P AcTase (pta) {Tt} 65 Glycolysis BB337 enolase (eno) {Bs} 79 BB445 fructose-bisP aldolase (fba) {Ec} 80 BB730 glucose-6-P isomerase (pgi) {Pf} 62 BB057 glyceraldehyde 3-P DHase (gap) {Bb} 99 BB630 1-phosphofructoKase (fruK) {Hi} 52 BB056 phosphoglycerate Kase (pgk) {Bb} 99 BB658 phosphoglycerate mutase (gpmA) {Ec} 79 BB348 pyruvate Kase (pyk) {Bs} 62 BB727 pyroP-fructose 6-P 1-PPTase (pfk) {Eh} 65 BB020 pyroP-fructose 6-P 1-PPTase, b sub (pfpB) {Bb} 100 BB055 trioseP isomerase {Bb} 100 Pentose phosphate pathway BB222 glucose-6-P 1-DHase, put {As} 48 BB636 glucose-6-P 1-DHase (zwf) {Hi} 64 BB561 phosphogluconate DHase (gnd) {Sd} 71 BB657 ribose 5-P isomerase (rpi) {Mj} 61 Sugars BB407 mannose-6-P isomerase (manA) {Ec} 54 BB444 nucleotide sugar epimerase {Vc} 69 BB676 phosphoglycolate PPase (gph) {Hi} 50 BB207 UTP-glucose-1-P uridylylTase (gtaB) {Bs} 63 BB545 xylulokinase (xylB) {Bs} 43 Fatty acid and phospholipid metabolism General BB037 1-acyl-sn-glycerol-3-P AcTase (plsC) {Bb} 100 BB685 3-OH-3-methylglutaryl-CoA RDase (mvaA) {Pm} 52 BB683 3-OH-3-methylglutaryl-CoA Sase {At} 53 BB109 Ac-CoA C-AcTase (fadA) {Hi} 67 BB704 acyl carrier prt {Syn} 65 BB721 CDP-diacylglycerol-glycerol-3-P 3-phosphatidylTase {Bs} 55 BB327 glycerol-3-P O-acylTase, put {So} 50 BB368 glycerol-3-P DHase, NAD(P)+ (gpsA) {Bs} 54 BB137 long-chain-fatty-acid CoA ligase {Syn} 54 BB593 long-chain-fatty-acid CoA ligase {Syn} 56 BB688 melvalonate Kase {Mj} 51 BB686 mevalonate pyroP DCase {Sc} 52 BB119 phosphatidate cytidylylTase (cdsA), AFS{Ec} 61 BB249 phosphatidylTase {Hp} 52 BB687 phosphomevalonate Kase, put {Sc} 53 Purines, pyrimidines, nucleosides, nucleotides Nucleotide and nucleoside interconversion BB417 adenylate kinase (adk) {Bs} 64 BB128 cytidylate kinase (cmk-1) {Bs} 58 BB819 cytidylate kinase (cmk-2) {Mj} 57 BB463 nucleoside-diP kinase (ndk) {Bs} 70 BB793 thymidylate kinase (tmk) {Mj} 59 BB571 uridylate kinase (smbA) {Mj} 54 Purine ribonucleotide biosynthesis BB544 phosphoribosyl pyroP Sase (prs) {Mp} 59 cp26 BBB18 GMP Sase (guaA) {Bb} 100 BBB17 IMP DHase (guaB) {Bb} 100 Pyrimidine ribonucleotide biosynthesis BB575 CTP Sase (pyrG) {Mj} 71 Salvage of nucleosides and nucleotides BB777 adenine phosphoribosylTase (apt) {Ta} 63 BB618 cytidine deaminase (cdd) {Mp} 61 BB239 deoxyguanosine/deoxyadenosine kinase(I) sub 2 (dck) {La} 59 BB375 pfs prt (pfs-1) {Ec} 64 BB588 pfs prt (pfs-2) {Hi} 59 BB791 thymidine kinase (tdk) {Bs} 47 BB015 uridine kinase (udk) {Bb} 100 lp36 BBK17 adenine deaminase (adeC) {Bs} 57 Regulatory functions General BB184 carbon storage regulator (csrA) {Hi} 63 BB647 ferric uptake regulation prt (fur) {Sp} 48 BB198 guanosine-3?,5?-bis(diP) 3?- pyrophosphohydrolase (spoT) {Ec} 61 BB737 histidine phosphoKase/PPase, put {Ml} 49 BB176 methanol DHase regulator (moxR) {Bb} 99 BB416 pheromone shutdown prt (traB) {Ef} 61 BB042 P transport system regulatory prt (phoU) {Pa} 57 BB379 prt Kase C1 inhibitor (pkcI) {Bb} 100 BB419 response regulatory prt (rrp-1) {Syn} 57 BB763 response regulatory prt (rrp-2) {Ec} 67 BB764 sensory transduction histidine Kase, put {Bs} 60 BB420 sensory transduction histidine Kase, put {Syn} 61 BB693 xylose operon regulatory prt (xylR-1) {Th.} 48 BB831 xylose operon regulatory prt (xylR-2) {Syn} 51 lp54 BBA07 chpAI prt, put {Ec} 55 Replication Degradation of DNA BB411 endonuclease precursor (nucA) {As} 53 DNA replication, restriction, modification, recombination, and repair BB422 3-methyladenine DNA glycosylase (mag) {At} 56 BB827 ATP-dep helicase (hrpA) {Ec} 61 BB437 chromosomal replication init prt (dnaA) {Bb} 100 BB435 DNA gyrase, sub A (gyrA) {Bs} 67 BB436 DNA gyrase, sub B (gyrB) {Bb} 99 BB344 DNA helicase (uvrD) {Ec} 55 BB552 DNA ligase (lig) {Ta} 56 BB211 DNA mismatch repair prt (mutL) {Hi} 55 BB797 DNA mismatch repair prt (mutS) {Hi} 57 BB098 DNA mismatch repair prt, put {Syn} 51 BB548 DNA polymerase I (polA) {Hi} 61 BB579 DNA polymerase III, sub a (dnaE) {Ec} 62 BB438 DNA polymerase III, sub b (dnaN) {Bb} 100 BB461 DNA polymerase III, sub g /t (dnaX) {Bs} 61 BB710 DNA primase (dnaG) {Bs} 56 BB581 DNA recombinase (recG) {Syn} 60 BB828 DNA topoisomerase I (topA) {Syn} 64 BB035 DNA topoisomerase IV (parC) {Bb} 58 BB036 DNA topoisomerase IV (parE) {Bb} 56 BB745 endonuclease III (nth) {Syn} 59 BB837 excinuclease ABC, sub A (uvrA) {Ec} 4 BB836 excinuclease ABC, sub B (uvrB) {Ec} 71 BB457 excinuclease ABC, sub C (uvrC) {Syn} 57 BB534 exodeoxyribonuclease III (exoA) {Bs} 67 BB632 exodeoxyribonuclease V, a chain Nature � Macmillan Publishers Ltd 1997 (recD) {Ec} 54 BB633 exodeoxyribonuclease V, b chain (recB) {Hi} 51 BB634 exodeoxyribonuclease V, g chain (recC) {Hi} 51 BB829 exonuclease SbcD (sbcD) {Ec} 55 BB830 exonuclease SbcC (sbcC) {Ec} 52 BB177 glucose-inhibited div prt B (gidB) {Bb} 99 BB178 glucose-inhibited div prt A (gidA) {Bb} 100 BB022 Holliday junction DNA helicase (ruvB) {Bb} 100 BB023 Holliday junction DNA helicase (ruvA) {Bb} 100 BB014 primosomal prt N (priA) {Bb} 100 BB131 recA prt (recA) {Bb} 100 BB607 rep helicase, ss DNA-dep ATPase (rep) {Hi} 61 BB111 replicative DNA helicase (dnaB) {Ec} 58 BB114 ss DNA-BP (ssb) {Syn} 62 BB254 ss-DNA-specific exonuclease (recJ) {Hi} 52 BB623 transcription-repair coupling factor (mfd) {Hi} 60 BB053 uracil DNA glycosylase (ung) {Hi} 68 lp28-2 BBG32 replicative DNA helicase, put {Bs} 59 lp25 BBE29 adenine specific DNA MTase, put {Hp} 57 Transcription General BB052 spoU prt (spoU) {Ec} 54 Degradation of RNA BB805 polyribonucleotide nucleotidylTase 68 (pnpA) {Bs} BB046 ribonuclease H (rnhB) {Hi} 66 BB705 ribonuclease III (rnc) {Bs} 62 BB441 ribonuclease P prt component (rnpA) {Bb} 100 DNA-dependent RNA polymerase BB502 DNA-directed RNA polymerase (rpoA) {Bs} 64 BB389 DNA-directed RNA polymerase (rpoB) {Bb} 97 BB388 DNA-directed RNA polymerase (rpoC) {Ec} 71 BB771 RNA polymerase sigma factor (rpoS) {Pa} 61 BB712 RNA polymerase sigma-70 factor (rpoD) {Bb} 100 BB450 RNA polymerase sigma-54 factor (ntrA) {Av} 57 Transcription factors BB107 N utilization substance prt B (nusB) {Ec} 62 BB800 N-utilization substance prt A (nusA) {Bs} 62 BB394 transcription antitermination factor (nusG) {Ec} 64 BB132 transcription elongation factor (greA) {Ec} 56 BB355 transcription factor, put {Mx} 47 BB230 transcription termination factor Rho (rho) {Bb} 100 RNA processing BB706 polynucleotide adenylylTase (papS) {Bs} 57 Translation General BB590 dimethyladenosine Tase (ksgA) {Bs} 61 BB802 ribosome-B factor A (rbfA) {Bs} 62 Amino acyl tRNA synthetases BB220 alanyl-tRNA Sase (alaS) {Ec} 62 BB594 arginyl-tRNA Sase (argS) {Mj} 55 BB101 asparaginyl-tRNA Sase (asnS) {Ec} 73 BB446 aspartyl-tRNA Sase (aspS) {Ec} 66 BB599 cysteinyl-tRNA Sase (cysS) {Hi} 58 BB372 glutamyl-tRNA Sase (gltX) {Rm} 63 BB371 glycyl-tRNA Sase (glyS) {Ta} 68 BB135 histidyl-tRNA Sase (hisS) {Mj} 59 BB833 isoleucyl-tRNA Sase (ileS) {Sc} 66 BB251 leucyl-tRNA Sase (leuS) {Bs} 70 BB659 lysyl-tRNA Sase {Mj} 54 BB587 methionyl-tRNA Sase (metG) {Sc} 67 BB514 phenylalanyl-tRNA Sase, b sub (pheT) {Bb} 100 BB513 phenylalanyl-tRNA Sase, a sub (pheS) {Bb} 100 BB402 prolyl-tRNA Sase (proS) {Sc} 65 BB226 seryl-tRNA Sase (serS) {Bs} 62 BB720 threonyl-tRNA Sase (thrZ) {Bs} 67 BB005 tryptophanyl-tRNA Sase (trsA) {Cl} 65 BB370 tyrosyl-tRNA Sase (tyrS) {Bs} 62 BB738 valyl-tRNA Sase (valS) {Bs} 67 Degradation of proteins, peptides, and gly- copeptides BB608 aminoacyl-histidine dipeptidase (pepD) {Hi} 55 BB366 aminopeptidase I (yscI) {Bb} 100 BB069 aminopeptidase II {Bs} 57 BB611 ATP-dep Clp protease proteolytic component (clpP-1) {Hi} 79 BB757 ATP-dep Clp protease proteolytic component (clpP-2) {Hi} 67 BB369 ATP-dep Clp protease, sub A (clpA) {Ec} 56 BB612 ATP-dep Clp protease, sub X (clpX) {Ec} 75 BB834 ATP-dep Clp protease, sub C (clpC) {Pp} 67 BB253 ATP-dep protease LA (lon-1) {Bb} 100 BB613 ATP-dep protease LA (lon-2) {Hi} 65 BB359 carboxyl-terminal protease (ctp) {Syn} 65 BB203 Lambda CII stability-governing prt (hflK) {Ec} 56 BB204 Lambda CII stability-governing prt (hflC) {Ec} 56 BB248 oligoendopeptidase F (pepF) {Ll} 58 BB067 peptidase, put {Sc} 56 BB104 periplasmic serine protease DO (htrA) {Hi} 60 BB430 proline dipeptidase (pepQ) {Hi} 49 BB769 sialoglycoprotease (gcp) {Hi} 60 BB627 vacuolar X-prolyl dipeptidyl aminopeptidase I (pepX) {Ml 55 BB118 zinc protease, put {Hi} 54 BB536 zinc protease, put {Hi} 52 Nucleoproteins BB232 hbbU prt {Bb} 100 Protein modification BB105 methionine aminopeptidase (map) {Bs} 68 BB065 polypeptide deformylase (def) {Syn} 67 BB648 serine/threonine kinase, put {Pf} 51 Ribosomal proteins: synthesis and modification BB392 ribosomal prt L1 (rplA) {Bs} 71 BB481 ribosomal prt L2 (rplB) {Bb} 99 BB478 ribosomal prt L3 (rplC) {Bb} 99 BB479 ribosomal prt L4 (rplD) {Bb} 100 BB490 ribosomal prt L5 (rplE) {Hi} 80 BB493 ribosomal prt L6 (rplF) {Sc} 72 BB390 ribosomal prt L7/L12 (rplL) {Sc} 75 BB112 ribosomal prt L9 (rplI) {Ec} 57 BB391 ribosomal prt L10 (rplJ) {Bs} 61 BB393 ribosomal prt L11 (rplK) {Tm} 73 BB339 ribosomal prt L13 (rplM) {Hi} 72 BB488 ribosomal prt L14 (rplN) {Tm} 79 BB497 ribosomal prt L15 (rplO) {Bs} 68 BB485 ribosomal prt L16 (rplP) {Syn} 81 BB503 ribosomal prt L17 (rplQ) {Ec} 63 BB494 ribosomal prt L18 (rplR) {Bs} 69 BB699 ribosomal prt L19 (rplS) {Ec} 74 BB188 ribosomal prt L20 (rplT) {Ec} 70 BB778 ribosomal prt L21 (rplU) {Ec} 58 BB483 ribosomal prt L22 (rplV) {Bb} 100 BB480 ribosomal prt L23 (rplW) {Bb} 100 BB489 ribosomal prt L24 (rplX) {Ec} 64 BB780 ribosomal prt L27 (rpmA) {Hi} 82 BB350 ribosomal prt L28 (rpmB) {Ec} 62 BB486 ribosomal prt L29 (rpmC) {Bs} 65 BB496 ribosomal prt L30 (rpmD) {Bs} 60 BB229 ribosomal prt L31 (rpmE) {Bs} 69 BB703 ribosomal prt L32 (rpmF) {Bs} 62 BB396 ribosomal prt L33 (rpmG) {Bs} 76 BB440 ribosomal prt L34 (rpmH) {Bb} 100 BB189 ribosomal prt L35 (rpmI) {Ba} 74 BB499 ribosomal prt L36 (rpmJ) {Bs} 89 BB127 ribosomal prt S1 (rpsA) {Ec} 55 BB123 ribosomal prt S2 (rpsB) {Pa} 79 BB484 ribosomal prt S3 (rpsC) {Hi} 71 BB615 ribosomal prt S4 (rpsD) {Hi} 63 BB495 ribosomal prt S5 (rpsE) {Bs} 77 BB115 ribosomal prt S6 (rpsF) {Os} 50 BB386 ribosomal prt S7 (rpsG) {Sc} 75 BB492 ribosomal prt S8 (rpsH) {Syn} 66 BB338 ribosomal prt S9 (rpsI) {Hi} 71 BB477 ribosomal prt S10 (rpsJ) {Bb} 100 BB501 ribosomal prt S11 (rpsK) {Hi} 77 BB387 ribosomal prt S12 (rpsL) {An} 89 BB500 ribosomal prt S13 (rpsM) {Cp} 76 BB491 ribosomal prt S14 (rpsN) {Bs} 72 BB804 ribosomal prt S15 (rpsO) {Tt} 77 BB695 ribosomal prt S16 (rpsP) {Bs} 70 BB487 ribosomal prt S17 (rpsQ) {Mc} 76 BB113 ribosomal prt S18 (rpsR) {Bs} 78 BB482 ribosomal prt S19 (rpsS) {Bb} 99 BB233 ribosomal prt S20 (rpsT) {Bb} 100 BB256 ribosomal prt S21 (rpsU) {Mx} 68 BB516 rRNA methylase (yacO) {Mc} 66 tRNA modification BB821 2-methylthio-N6-isopentyladenosine tRNA modification enzyme (miaA) {Ec} 53 BB084 AT (nifS) {Syn} 61 BB343 glu-tRNA amidoTase, sub C (gatC) {Bs} 56 BB341 glu-tRNA amidoTase, sub B (gatB) {Bs} 63 BB342 glu-tRNA amidoTase, sub A (gatA) {Bs} 61 BB064 methionyl-tRNA formylTase (fmt) {Ec} 56 BB787 peptidyl-tRNA hydrolase (pth) {Bb} 100 BB012 pseudouridylate Sase I (hisT) {Bb} 100 BB021 SAM: tRNA ribosylTase-isomerase {Bb} 96 BB809 tRNA-guanine transglycosylase (tgt) {Zm} 60 BB698 tRNA (guanine-N1)-MTase (trmD) {Mg} 68 BB803 tRNA pseudouridine 55 Sase (truB) {Ec} 57 Translation factors BB088 GTP-B membrane prt (lepA) {Hi} 76 BB196 peptide chain release factor 1 (prfA) Hi} 73 BB074 peptide chain release factor 2 (prfB) {Sc} 70 BB121 ribosome releasing factor (frr) {Mt} 68 BB169 translation initiation factor 1 (infA) {Ec} 87 BB801 translation initiation factor 2 (infB) {Bs} 73 BB190 translation initiation factor 3 (infC) {Pv} 72 BB691 translation elongation factor G (fus-2) {Tm} 67 BB214 translation elongation factor P (efp) {Ec} 56 BB476 translation elongation factor TU (tuf) {Bb} 100 BB122 translation elongation factor TS (tsf) {Hi} 57 BB540 translation elongation factor G (fus-1) {Tm} 68 Transport and binding proteins General BB573 ABC transporter, ATP-BP {Bs} 53 BB742 ABC transporter, ATP-BP {Syn} 57 BB466 ABC transporter, ATP-BP {Hi} 74 BB754 ABC transporter, ATP-BP {Bl} 60 BB080 ABC transporter, ATP-BP {Mj} 63 BB269 ATP-BP (ylxH-1) {Bb} 100 BB726 ATP-BP (ylxH-2) {Bb} 54 lp38 BBJ26 ABC transporter, ATP-BP {Mj} 62 Amino acids, peptide, and amines BB729 glutamate transporter (gltP) {Bs} 55 BB401 glutamate transporter, put {Bs} 53 BB146 GBP ABC transporter, ATP-BP Nature � Macmillan Publishers Ltd 1997 (proV) {Sc} 71 BB145 GBP ABC transporter, permease prt (proW) {Ec} 66 BB144 GBP ABC transporter, BP (proX) {Ec} 43 BB334 OP ABC transporter, ATP-BP (oppD) {Bs} 75 BB335 OP ABC transporter, ATP-BP (oppF) {Bs} 80 BB332 OP ABC transporter, permease prt (oppB-1){Ec} 68 BB747 OP ABC transporter, permease prt (oppB-2){Bs} 54 BB333 OP ABC transporter, permease prt (oppC-1){Hi} 64 BB746 OP ABC transporter, permease prt (oppC-2){Bs} 52 BB328 OP ABC transporter, periplasmic BP (oppA-1) {Bb} 74 BB329 OP ABC transporter, periplasmic BP (oppA-2) {Bb} 94 BB330 OP ABC transporter, periplasmic BP (oppA-3) {Bb} 81 BB642 SP ABC transporter, ATP-BP (potA) {Ec} 69 BB641 SP ABC transporter, permease prt (potB) {Ec} 65 BB640 SP ABC transporter, permease prt (potC) {Ec} 63 BB639 SP ABC transporter, periplasmic BP (potD) {Ec} 53 lp54 BBA34 OP ABC transporter, periplasmic BP (oppA-4) {Bc} 66 cp26 BBB16 OP ABC transporter, periplasmic BP (oppA) {Bb} 78 Anions BB218 P ABC transporter, ATP-BP (pstB) {Pa} 74 BB216 P ABC transporter, permease prt (pstC) {Ec} 58 BB217 P ABC transporter, permease prt (pstA) {Syn} 63 BB215 P ABC transporter, periplasmic P-BP (pstS) {Syn} 48 Carbohydrates, organic alcohols, and acids BB240 glycerol uptake facilitator (glpF) {Bs} 57 BB604 L-lactate permease (lctP) {Ec} 57 BB318 methylgalactoside ABC transporter, ATP-BP (mglA) {Hi} 54 BB814 pantothenate permease (panF) {Ec} 63 BB448 phosphocarrier prt HPr (ptsH-1) {Mg} 56 BB557 phosphocarrier prt HPr (ptsH-2) {Hi} 69 BB558 phosphoenolpyruvate-prt PPase (ptsI) {Sc} 65 BB408 PTS system, fru-specific IIABC (fruA-1) {Ec} 65 BB629 PTS system, fru-specific IIABC (fruA-2) {Ec} 68 BB559 PTS system, glu-specific IIA (crr) {Bb} 100 BB645 PTS system, glu-specific IIBC (ptsG) {Sc} 67 BB116 PTS system, mal/glu-specific IIABC (malX) {Ec} 56 BB677 RG ABC transporter, ATP-BP (mglA) {Mg} 68 BB678 RG ABC transporter, permease prt (rbsC-1) {Mg} 51 BB679 RG ABC transporter, permease prt (rbsC-2) {Mp} 52 cp26 BBB04 PTS system, cello-specific IIC (celB) {Bs} 62 BBB05 PTS system, cello-specific IIA (celC) {Bs} 61 BBB06 PTS system, cello-specific IIB (celA) {Bs} 73 BBB29 PTS system, glu-specific IIBC, put {Ec} 70 Cations BB724 K+ transport prt (ntpJ) {Eh} 60 BB380 Mg2+ transport prt (mgtE) {Bb} 100 BB164 Na+/Ca+ exchange prt, put {Mj} 59 BB447 Na+/H+ antiporter (napA) {Eh} 57 BB637 Na+/H+ antiporter (nhaC-1) {Bf} 48 BB638 Na+/H+ antiporter (nhaC-2) {Hi} 50 Other BB451 chromate transport prt, put {Mj} 58 Other categories Adaptations and atypical conditions BB237 acid-inducible prt (act206) {Rm} 45 BB786 general stress prt (ctc) {Bs} 51 BB785 stage V sporulation prt G {Bm} 74 BB810 virulence factor mviN prt (mviN) {Hi} 51 Colicin-related functions BB766 colicin V production prt, put {Hi} 52 BB546 outer membrane integrity prt (tolA) {Hi} 44 Drug and analog sensitivity BB140 acriflavine resistance prt (acrB) {Hi} 53 BB258 bacitracin resistance prt (bacA) {Ec} 56 BB586 femA prt (femA) {Se} 47 BB141 membrane fusion prt (mtrC) {Hi} 47 lp28-4 BBI26 multidrug-efflux transporter {Hp} 55 lp25 BBE22 pyrazinamidase/nicotinamidase (pncA) {Mt} 56 Transposon-related functions lp38 BBJ05 transposase-like prt, put {Bb} 89 lp36 BBK25 transposase-like prt, put {Bb} 80 lp28-1 BBF18 transposase-like prt, put {Bb} 96 BBF19 transposase-like prt, put {Bb} 96 lp28-2 BBG05 transposase-like prt {Bb} 99 lp28-3 BBH40 transposase-like prt, put {Bb} 57 lp17 BBD20 transposase-like prt, put {Bb} 99 BBD23 transposase-like prt, put {Bb} 88 Unknown BB528 aldose RDase, put {Bs} 57 BB684 carotenoid biosyn prt, put {Ss} 58 BB671 chemotaxis operon prt (cheX) {Bb} 99 BB250 dedA prt (dedA) {Ec} 54 BB168 dnaK suppressor, put {Ec} 53 BB508 GTP-BP {Tp} 59 BB219 gufA prt {Mx} 54 BB421 hydrolase {Hi} 58 BB524 inositol monoPPase {Hs} 47 BB454 lipopolysaccharide biosyn-related prt {Mj} 49 BB702 lipopolysaccharide biosyn-related prt {Hi} 62 BB045 P115 prt {Mh} 53 BB336 P26 {Bb} 100 BB363 periplasmic prt {Bb} 100 BB033 small prt (smpB) {Rp} 70 BB297 smg prt {Bb} 100 BB443 spoIIIJ-associated prt (jag) {Bs} 56 lp54 BBA76 thy1 prt (thy1) {Dd} 68 lp28-4 BBI06 pfs prt (pfs) {Ec} 59 cp9 BBC09 rev prt (rev) {Bb} 62 BBC10 rev prt (rev) {Bb} 66 "
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Genetics
Gene Inheritance and Transmission
Gene Expression and Regulation
Nucleic Acid Structure and Function
Chromosomes and Cytogenetics
Evolutionary Genetics
Population and Quantitative Genetics
Genomics
Genes and Disease
Genetics and Society
Cell Biology
Cell Origins and Metabolism
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