genetic map of bacteriophagegenetic mapof phage lambda 579 table 1. genesofphageaandtheirfunction...

MICROBIOLOGICAL REVIEWS, Sept. 1978, p. 577-5910146-0749/78/0042-0577$02.00/0Copyright © 1978 American Society for Microbiology

Vol.42, No. 3

Printed in U.S.A.

Genetic Map of Bacteriophage LambdaHARRISON ECHOLS* AND HELIOS MURIALDO

Department ofMolecular Biology, University of California, Berkeley, California 94720, * and Department ofMedical Genetics, University of Toronto, Toronto M5S 1A8, Canada

INTRODUCTION.5..577PHYSICAL STATES AND ACTIVITY OF THE A GENOME 577GENETIC MAP OF THE A GENOME.577ACTIITrY MAP OF THE A GENOME.583COMMENTS ON GENETIC ORGANIZATION ...........5*583LITERATURE CITED.584

INTRODUCTIONThe study of bacteriophage A has been a cen-

tral endeavor of molecular biology for a numberof years. Phage A has been the creature of choicefor many investigators interested in deoxyribo-nucleic acid (DNA) transcription, replication,and recombination, in nucleoprotein assembly,and in the organization of these processes intotemporally regulated pathways. As a result ofthis intensive study, a great deal of informationis now available about A genes and how theywork; however, the communication of thisknowledge is sometimes hindered by a "culturegap" between "lambdologists" and those lackingan understanding of the array of gene names andsites for protein activity. In an effort to remedythis difficulty, we present an annotated geneticmap of phage A. We begin with a brief summaryof the A life cycle; present two maps, one of geneorder and one of gene activity; and concludewith a short commentary on the genetic orga-nization.

PHYSICAL STATES AND ACTIVITY OFTHE X GENOME

The genome of phage A is a double-strandedDNA molecule about 47,000 base pairs in length.In the phage particle, A DNA has single-stranded, complementary ends 12 bases inlength, termed mature or cohesive ends m andm'. Within an infected cell, A DNA forms a circlethrough pairing ofthe single-stranded DNA, andis replicated and transcribed as a circular mole-cule during the replication-oriented early phaseof A development.

After this early stage, A development mayproceed along the productive (or lytic) pathwayor along the alternative lysogenic pathway. Theencapsulation-oriented late stage of the produc-tive pathway involves a transcription switch tosynthesis of head, tail, and lysis proteins and areplication switch to a rolling-circle mode thatgenerates multimeric A genomes (concatemers)

that are the obligatory precursors for thecleaved, linear molecules packaged into a phagehead (Fig. 1). The lysogenic pathway involves arepression of transcription and a site-specificrecombination event that inserts A DNA intothe host Escherichia coli genome. This integra-tive recombination between the phage and hostattachment sites (att) generates a genetic struc-ture that is permuted from the linear orderfound in the phage particle because the phageattachment site (a a' or P P) is approximatelyin the center of the mature DNA molecule (Fig.1). The prophage has structurally distinct at-tachment sites: a left attL site (b a' or B P')and a right attR site (a b' or P B'); these inturn can recombine to detach the prophageDNA when the virus is induced to lytic devel-opment, regenerating the phage attP site (a a'or P P') and the original host attB site (b b' orB B').More detailed descriptions of the diverse life-

styles of phage A can be found in the generalreview articles by Echols (47; in J. R. Sokatchand L. N. Ornston, ed., The Bacteria, in press)and Herskowitz (88). The lysogenic pathway hasbeen recently reviewed by Weisberg et al. (233);the lytic pathway has not been selectively re-viewed for some time, but the general featuresare covered in the review by Echols (46).

GENETIC MAP OF THE X GENOMEThe order of genes along the linear A DNA

molecule is shown in the upper part of Fig. 2;the function of certain gene clusters is indicatedbelow the map. The lower part of Fig. 2 gives ablowup of the right half of the A map, designedto focus on the activity sites for the develop-mental events noted in the preceding section.To construct Fig. 2, we used three principaltypes of information: (i) "traditional" geneticmapping; (ii) physical mapping by heteroduplexanalysis of genetically characterized deletionmutations; and (iii) molecular weights of gene

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578 ECHOLS AND MURIALDO

Lateproteins

Monomer DNA onInjected DNA replicotion

Eorly~~~~~~~Eoffmm' Eor1y mm' f" proteinsK> proteins o

°mmmiil

C ) Lyticproteins

o,f fIIntegrotion

on

FIG. 1. Developmental pathways for bacteriophage A. The injected DNA forms a covalently closed circlethrough pairing of the mature ends, m and mi', followed by ligation. After an early phase common to bothpathways, viral development may follow the productive or lysogenic pathways. In the productive pathway,synthesis of encapsulation and lysis proteins is turned on, synthesis of early proteins is turned off, andreplication switches to a rolling-circle mode that generates the multimeric DNA used as a substrate forencapsulation of linear DNA with free mature ends. In the lysogenic pathway, synthesis of lytic proteins isturned off, and the circular viral DNA is inserted into the host genome by a specific recombination event.

GENETIC MAPNu! P.u3 Ef Fl Fl z U V G rt L K i uooint xis redX redB gem i! ciiicralrox cro cl OP SR

mA W CO]D 2 ImtXW-t;tX'l4g4HS/aD?J 4+ 1 ~~~~'V ClI o$g lm0 10 20 30 40 50 60 70 80 90 100

Phage heod Phoge tail Integration, Replication sisexcision, Regulation Lateand Reglaton lateo

recombination regulation

GENE ACTIVITY MAP Through heodand toil

00 PL CI PR CrO fg1 Cl 'n 0p or P fe2 P'sint xis cmIII ILAN9 0 m

50 60 70 2 80 90 too

Pt SOL! PM Pt

FIG. 2. Genetic map of bacteriophage A. The genes that code for proteins of defined function are shown inthe upper part of the figure; the vertical line marks the approximate center of the genes (see Table 1). The bregion is silent in terms of defined viral functions, although it does code for several proteins (see text andTable 1). The regulatory sites and their function are indicated in the lower part of the figure; these aredescribed in the text and in Table 1. The different stages of transcriptional activity and the DNA regionsinvolved are indicated by the arrows; the actual length of DNA transcribed can be determined from theintersection of the promoter (p) and terminator (t) lines with the horizontal calibrated line representing theA genome.

products. The principles (and examples) aregiven in the articles by Campbell (20), Davidsonand Szybalski (38), and Szybalski and Szybalski(211). The functions of the genes and sites aresummarized with references in Table 1.Based on the physical mapping data of Par-

kinson and Davis (156) and the estimated mo-lecular weights of the gene products (Table 1),the head and tail region is "oversaturated"(codes for more amino acids than available nu-cleotides). We believe that the discrepancy mostlikely results from overestimates of protein sizeby the standard method of polyacrylamide gelelectrophoresis in sodium dodecyl sulfate, ratherthan from overlapping genes, because several

examples of this type of overestimate exist (e.g.,the V protein has an electrophoretic estimate of32,000 daltons, but a calculated value fromamino acid composition of 26,000 daltons).Based on this assessment, we have reduced thesize of some genes (3 to 10%) to conform to thephysical map; these reduced values are used forthe "Coordinates" column of Table 1. The mo-lecular weight values originally reported for theproteins are given in the "Gene function and/orprotein activity" column.Most readers of this article are aware already

that A nomenclature has not evolved in a logi-cally consistent way. Genes for proteins essentialto productive growth were originally given up-

DNA encapsulation

DNA integrationmm

b bI

Phage

Prophoge

_110. bo' mm' oab'

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GENETIC MAP OF PHAGE LAMBDA 579

TABLE 1. Genes ofphage A and their function

Gene symbol Approx map co- Gene function and/or protein activity Referencesbordinatesa

m 0

Nul

A

w

B

0/0.5

0.5/4.7

4.7/5.0

5.0/8.3

8.3/11.3C

Nu3

D

E

FI

FII

z

11.3/12.3

12.3/12.8

12.8/14.8

14.8/15.7

15.7/16.3

16.3/17.4

17.4/18.4U

V

G

18.4/19.9

19.9/21.7

T 21.7/22.6

H 22.6/27.3

M 27.3/27.9

L

K

I

27.9/29.6

29.6/31.2

31.2/31.831.8/39.4

Left cohesive end of the mature DNA mol-ecule; the first 12 nucleotides of the 5'end of the I (transcribed leftward) strandprotrude as a single-stranded chain,complementary to m'.

Involved in DNA packaging and cohesiveend formation; may activate A protein.

DNA packaging into proheads and forma-tion of cohesive ends; protein is 79,000daltons (79K).

Modifies DNA-filled heads in an unknownway to allow FII action; protein is 5-10K.

Structural component of the capsid; B pro-tein and a cleaved derivative B formthe head-tail connector-, B is 59-62K; B"is 53-56K.

Structural component of capsid; the56-61K C protein is present in the capsidas two cleaved derivatives, fused to acleaved derivative of E; the two cleav-age-fusion products, termed Xl and X2,are 29 and 27K, respectively.

Transient morphopoietic core for capsidassembly; protein is 19K.

Major component of the phage head; the11-12K protein is incorporated into thecapsid during or after DNA packaging.

Major component of the capsid; 10 to 12 ofthe 420 molecules of the 37K E proteinare present in the capsid fused to C,forming Xl and X2 (see C).

Packaging and maturation of DNA; the17K protein may confer specificity on Aprotein.

Structural component of DNA-filledheads; the 11.5K protein mediates tailattachment.

Structural component of the proximal endof the tail; the 20K protein is involved inproper positioning of the right end of theDNA molecule in the tail.

Structural component of the tail; the14-16K protein is the tail length deter-mination factor.

Major protein of the tail tube; protein is25-32K.

Involved in the assembly of the tail initia-tor-, the 33K protein is possibly a struc-tural component. .

Structural component of the tail; the 16Kprotein is involved in the assembly ofthe tail initiator.

Cleaved form of the 87-90K H protein, the78-79K H*, is a structural component ofthe tail, involved in DNA injection.

Structural component of the tail; the 10Kprotein is involved in tail initiator assem-bly.

Structural component of the tail initiator;protein is 29K.

Temporarily associated with the tail initi-ator, function unknown; protein is 27K.

Involved in assembly of the tail initiator.Structural component of the tail; the

130-140K protein forms the tail fiberand determines host range of adsorption.

13,31,38,57,60,61,69,87,146,147, 151, 206, 218, 228, 229,237,238

8, 145, D

5-7, 19, 67,90, 96, 103, 109-111,132, 139, 144, 145, 155, 197,204, 206, 210, 226, 229, 231

28, 93, 132, 155, 205, 226

7, 19, 67, 85, 86, 91, 120, 139,140, 141, 142, 145, 155, 169,204, 223, 231, 242

7, 19, 67, 84-86, 91, 120, 139,140, 141, 142, 144, 145, 155,169, 204, 223, 231, 242

7, 86, 91, 103, 140, 141, 144,145, 169, 242

4, 7, 19, 29, 91, 92, 95, 98, 111,129, 132, 139, 143-145, 204,207, 226, 231, 234

4, 7, 16, 19, 27, 29, 85, 86, 91, 94,98, 101, 103, 120, 132, 139,140, 141, 144, 145, 155, 169,204, 223, 226, 231, 234

7, 8, 14, 19, 142, 144, 155

12, 14, 15, 19, 24, 26, 28, 132,144, 145, 155, 226

113-116, 155, 218, 219

113-117, 120, 126, 139, 144,155

6, 113-117, 126, 143, 144, 155

67, 116, 120, 126, 139, 144, 155,231

67, 139, 144

19, 83, 103, 113, 116, 120, 126,139, 143, 144, 155, 183, 231

19, 113, 114, 116, 117, 120, 139,155, 231

19,103, 114, 116,120, 126,139,144, 155, 231

19, 103, 114, 116, 120, 126, 139,144, 155, 231

19, 103, 113, 116, 155, 223, 23117, 19, 42, 67, 82, 113, 114, 116,

120, 126, 139, 143, 144, 155,188, 231

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TABLE 1.-Continued

Gene symbol Approx map co- Gene function and/or protein activity Referencesbordinatesa39.4/57.3 Although this region of the chromosome is

called the silent region, it codes for sev-eral proteins of unknown function.

57.3 Determines location and specificity of site-specific recombination; 15-base homol-ogy with host site b b'.

57.4/59.8 Integrative and excisive recombination;the 40K protein provides sequence rec-ognition for a* a'.

59.8/60.2 Excisive recombination.(60.2) Promoter for transcription from the int

gene under positive regulation by cII andcIII proteins.

(64.7/66.1) General recombination; the 24K protein("A-exonuclease") is a 5'-exonuclease ac-tive on double-stranded DNA.

66.1/67.8 General recombination; the 28K protein("C'-protein") associates with A-exonu-clease.

67.8/68.7 Regulation of DNA replication; the 16K("gamma") protein inhibits the RecBCDNase, an antagonist of the rolling-cir-cle mode of replication.

(68.7/69.2) Loss of host cell viability, associated withan inhibition of cell division.

(68.8/70.7) Establishment of lysogeny (together withcII); the cII and cHII proteins activatetranscription from the cI and int genesand repress transcription from the lysis,head, and tail (and probably replication)genes (see cHI, PE, and pi).

(70.7/71.6) Partial alleviation of restriction of X DNAby K-12 restriction endonuclease.

(71.8) Termination for the earliest (immediate-early) stage of RNA synthesis initiatedat pi., a p-mediated event.

72.5/73.3 Positive regulation of early development;the 13K protein activates delayed-earlytranscription from recombination, repli-cation, and regulation genes; N proteinprevents termination events at tL, tRi,and tR2.

73.5 Promoter for transcription of the N geneduring the immediate-early stage of de-velopment and for the N through recom-bination region during the N-activateddelayed-early stage of development (seeN); repressed by Cro during the latestage of lytic development and by cIduring the maintenance stage of lyso-geny (see cI and cro).

73.5/73.6 Operator for regulation of transcriptionfrom PL; the OL sequence defines three17-base binding sites, OLI, oL2, oL3; the cIand Cro proteins bind at OL to preventbinding by RNA polymerase and thustranscription from pL.

(74.2) Terminator for transcription of the cI andrex genes (initiated at PM) during themaintenance stage of the lysogenic path-way.

(74.2/75.9) Restricts growth of T4rII mutants andhelps cell growth in limiting carbonsources; protein is 29K.

32,40,81,82, 119, 128, 134, 144,157, 173, 177, B

39, 40, 50, 99, 127, 192, 194

3, 45, 50, 59, 70, 71, 73, 74, 121,122, 138, 148, 194, 243

45, 59, 76, 10859, 190, 191

23, 49, 131, 165, 167, 193, 194

23, 49, 165, 193, 194

58, 112, 180, 195, 225, 244

75

33, 34, 36, 51, 55, 106, 118, 122,133, 170, 201

A

123, 126, 174

1, 19, 66, 80, 124, 126, 149, 166,174, 189, 196, 221, 222

10, 11, 124, 136, 174, 217

52, 96, 102, 107, 135, 136, 159,163, 172, 199, 203, 213, 214,235, 236

79, 102

77, 97, 130, B

b

a a'/(P P' or attP)

int

xisPi

redX

redB

gam

kil

CIII

ral

tL

N

PL

OL

tM

rex

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TABLE 1.-Continued

Gene symbol Approx map co- Gene function and/or protein activity Referencesbordinates'

cI 76.9/78.4

PM (P.)

OR

PR

cro (tof, fed)

tRI

Pa (Pre)

cH

Po

0

78.4

78.4/78.5

78.5

78.6/79.0

79.2

79.2

79.2/79.8

79.9

79.9/81.9

Maintenance of lysogeny through a repres-sion of RNA from early genes; the 26Kprotein binds as a dimer (or tetramer) toOL and OR, repressing transcription frompL andpR and regulating transcription ofthe cI and rex genes, positively at low cIlevels and negatively at high cI levels(see OL and OR).

Promoter for transcription of the cI andrex genes during the maintenance stageof lysogeny; the cI and Cro proteins bindat OR to regulate this transcription (seeOR, cI, and cro).

Operator for regulation of transcriptionfromPM andpR; the OR seqeuence definesthree 17-base binding sites, ORI, OR2, OM;the cI and Cro proteins bind at ORI andoR2 to prevent binding of RNA polym-erase and thus transcription from pi,; cIbinding at ORI (and/or oR2) enhancestranscription from PM, whereas cI andCro binding atoR3 prevents transcriptionfrompM.

Promoter for transcription of the cro gene(and limited cIIOP transcription) duringthe immediate-early stage of develop-ment and for the cro gene onwards dur-ing the N-activated delayed-early stageof development (see N); repressed byCro during the late stage of lytic devel-opment and by cI during the mainte-nance stage of lysogeny (see cI and cro).

Regulation of late stage of lytic develop-ment; Cro represses early transcriptionand is also required directly or indirectlyfor normal late replication; the 7K pro-tein binds as a dimer to OL and OR, re-pressing transciption form p,, PR, andpM (see oL and OR).

Terminator for most of the earliest ("im-mediate-early") stage of RNA synthesisinitiated at PR, a p-mediated event.

Promoter for transcription of the cI andrex genes during the establishment stageof lysogeny; positively regulated by cIIand cm proteins.

Establishment of lysogeny (together withcIII); the 11K cII protein (aided by cIII)activates transcription from the cI andint genes and represses transcriptionfrom the lysis, head, and tail (and prob-ably replication) genes (see cIII, pE andpx).

Promoter for transcription of the 4S or"OOP" RNA, an 81-base RNA, termi-nating in the absence of p, that so farlacks a clearly defined function (it hasbeen postulated to be involved in initia-tion of replication or the establishmentof repression).

Initiation of the early (simple-circle) modeof DNA replication (with P); the 34Kprotein probably interacts with the ori-gin sequence and P protein, and thecomplex directs the host DNA propa-gation enzymes to replicate A DNA; 0and P proteins may also be required forthe propagation stage of replication (seeP and ori).

30, 53, 55, 102, 106, 107, 137,161, 162, 171, 172, 182, 203,236

55, 79, 102, 135, 160, 170, 171,241

52, 64, 96, 102, 104, 107, 135,137, 160, 163, 171, 203, 213,214, 235, 236

10, 11, 124, 135, 174, 217, 227

18, 35, 52, 55, 63, 64, 65, 1(00,104, 123, 154, 158, 159, 176,186, 199, 200, 213, 214, 215

80, 149, 174, 178, 186

51, 170, 201, C

33, 34, 36, 51, 55, 106, 118, 122,133, 170, 186, 201, 240, B

37, 79, 184

19, 56, 68, 105, 152, 164, 186,212, 224, 240, B

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TABLE 1.-Continued

Gene symbol Approx map co- Gene function and/or protein activity References'Genesymbol ordinates'

80.9 Origin (initiation site) for the bidirectionalearly (simple-circle) mode of DNA rep-lication; activation of the o-rigin requiresO and P proteins (and probably RNAsynthesis through or near the site) (seeO and P).

81.9/83.3 Initiation of the early (simple-circle) modeof DNA replication (with 0); the 24Kprotein probably interacts with 0 pro-tein, and the resultant O/P/ori complexdirects the host propagation enzymes toreplicate A DNA; 0 and P proteins mayalso be required for the propagationstage of replication (see 0 and ori).

(83.3) Terminator for the residual fraction (aftertRi) of the earliest (immediate-early)stage of RNA synthesis initiated at PR,a p-mediated event.

90.8/92.1 Positive regulation of the late stage of lyticdevelopment; the 23K protein activateslate transcription (initiated at P'R) fromthe lysis, head, and tail genes; Q mightprovide for new initiation events or pre-vent termination of a small 198-base 6SRNA synthesized (at least in vitro) fromthe P'R region (see P'R)

(93.1) Promoter used for transcription of thehead, tail, and lysis genes, subject topositive regulation by Q protein (see Q).

(93.1/93.9) Cell lysis (together with R); the S proteinis probably involved in a turnoff of cer-tain host functions as a necessary pre-requisite for cell lysis, perhaps througha direct effect on the cell membrane; S-mutants accumulate large numbers ofintracellular phage.

(93.9/95.0) Cell lysis (together with S); the 18K (en-dolysin) protein is an endopeptidase thatproduces lysis through hydrolysis of thecross-linking bond in murein.

100 Right cohesive end of the mature DNAmolecule; the first 12 nucleotides of the5' end of the r strand protrude as asingle-stranded chain, complementaryto m.

41, 44, 168, 185, 208

56, 105, 152, 153, 212, 224, B

80, 149, 178

19, 42, 89, 105, 149, 150, 175,196, 198

89, 175, 198

2, 72, 78

9, 22, 54, 62, 216

13, 31, 38, 57, 60, 61, 69,87, 146,147, 151, 206, 218, 228, 230,237,238

'Approximate map coordinates were determined mainly from electron microscopic data on heteroduplex structures ofgenetically characterized deletions and from molecular weights of proteins; the extensive set of heteroduplex data by Szybalskiand co-workers has been particularly helpful in this effort (11, 38, 99, 211). Coordinates likely to be off by more than ±0.2 unitsare in parentheses.

b Reference numbers in roman type denote studies of gene function; boldface numbers denote studies of activity in vitro withpurified proteins; italic numbers denote nucleotide or amino acid sequences. Letters refer to manuscripts in preparation orsubmitted for publication but not yet in press: (A) L. De Brouwere, M. Zabeau, M. Van Montagu, and J. Schell; (B) C. Epp andM. L. Pearson; (C) M. Jones, R. Fischer, I. Herskowitz, and H. Echols; (D) R. A. Weisberg and N. Stemnberg.

percase designations (19); genes for regulatoryproteins needed for lysogeny were given lower-case designations (106); and "other" genes non-

essential for productive growth (or thought tobe) were given three-letter designations (e.g., int,red). We consider this situation unfortunate, butsuspect that an effort for complete consistencyat this stage will cause more confusion than itwill remedy. Thus we have adopted most of thecurrent nomenclature and have only sought to

explain it (Table 1). In order not to have thesame name for two things (e.g., gene P andattachment site P), we have used lowercase italicletters throughout for sites of protein activityand retained uppercase italic letters and italicthree-leter designations for genes that code forproteins. The proteins themselves are desig-nated by nonitalic letters, generally followed (inthe text) by protein; in the field of bacteriophagemorphogenesis, gene products are more usually

ori

p

tR2

Q

P R

S

R

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designated by the symbol of the gene precededby the lowercase letters gp (for gene product)(e.g., gpA = A protein).

ACTIVITY MAP OF THE X GENOMEThe activity map of A DNA shown in the

lower part of Fig. 2 indicates the known DNAsites at which the proteins essential for A devel-opment act. Promoter (initiation) sites for RNAsynthesis are designated p and termination sitest; the transcription pattern that characterizesproductive growth is shown above the line rep-resenting A DNA, and the transcripts specific forlysogenic development are shown below the line.During the initial "immediate-early" phase of

productive growth, ribonucleic acid (RNA)chains initiated at the early promoter sites pLand pRzare mainly terminated at the end of theN and cro genes (termination sites tL and tRi,respectively); some rightward RNA chains con-tinue through the replication genes (to tR2)(-). During the next "delayed-early" phase, theN protein provides for extension of the imme-diate-early transcripts into the remainder of theearly-gene region, providing for synthesis of rep-lication, recombination, and regulatory proteins(--). During the late phase, the Cro protein actsat the operator sites OL and OR to reduce initia-tion of the early RNA; Q protein provides fortranscription of the lysis, head, and tail regionsby a transcript initiated at the late promoter siteP'R and continuing through the entire late-generegion (- - -*) (the lysis genes are joined to thehead and tail genes in the simple-circle or roll-ing-circle molecule).

During the establishment phase of lysogenicdevelopment, the cII and cIII proteins activateleftward transcription of the cI and int genes,initiated at the promoter sites PE and pi (oo,and inhibit rightward transcription of lyticgenes. During the maintenance phase, the cIprotein acts at OL and OR to repress nearly all Atranscription by preventing synthesis of early-gene RNA from the early promoter sites pL andPR; the cI protein also regulates its own furthersynthesis by controlling cI gene transcriptionfrom the maintenance promoter PM (**e+, ex-erting positive regulation at low cI concentrationand negative regulation at high cI concentration.The operator sites OLand OR define three bindingsites for cI protein, and the different bindingconstants probably account for the functionaldiversity of the repressor-operator interaction.The symbol ori represents the initiation site

for the early mode ofDNA replication specifiedby the 0 and P proteins; the initiation site forthe late, continuous rolling-circle mode is notknown with any certainty. Specificity for inte-

grative recombination involves recognition ofthe attachment site (a-a') by the Int protein,leading to the breaking and joining event (a* a'x b b') that inserts the viral DNA into that ofthe host. The reverse excisive recombinationrequires recognition of the prophage attachmentsites (b a' and a- b') in a reaction involving theInt and Xis proteins. The generation of the freemature ends (m and m') most likely involvesspecific nucleolytic cleavage by the A protein ina reaction that also requires at least the presenceof phage head precursors (proheads) and possi-bly host factors.

COMMENTS ON GENETIC ORGANIZA-TION

Some remarkable features of genetic organi-zation in phage A are evident from a considera-tion of Fig. 2 and the accompanying discussion.We note the following points: (i) the clusteringof genes with similar function (e.g., head, tail,DNA); (ii) the proximity of genes for proteinsacting on X DNA to their site of action (e.g., cIand cro to OL and oR, int and xis to att, 0 and Pto ori); (iii) the remarkable economy in the useof most of X DNA; and (iv) the puzzling "silent"b region. More extensive discussions than thefollowing one may be found in the articles byThomas (220), Stahl and Murray (202), Dove(43), Casjens and Hendrix (26), Echols et al. (48),Campbell (21), and Echols (in press).The clustering of genes with similar functions

is of potential value in three ways: the regulatoryneeds of viral development are simplified be-cause a limited number of regulatory proteinsand sites are required to control a large numberof genes whose products act together (at least intime); genes for proteins that must recognizeeach other are rarely separated by recombina-tion; and the evolution of new phage species isfacilitated by recombinational transfer of func-tional "modules" (e.g., a phage can acquire anew tail with different adsorption properties).The proximity of genes to target sites on theDNA also serves these three potential purposes;in addition, a protein is synthesized close to itsactivity site, thus conferring a potential kineticincrement on protein activity because the pro-tein does not need to diffuse through a vastnumber of nonspecific interactions to reach itstarget site.Although A has not been demonstrated to

have the "gene-within-a-gene" economy of4OX174 and G4 (181, 187), the intensive use of ADNA is nevertheless impressive. With the ex-ception of the b region and a stretch between Pand Q, there appears to be very little DNA notused to code for proteins of known utility, and

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some genes probably remain to be identified(e.g., control of the switch to rolling-circle rep-lication). In fact the recombination region maybe oversaturated (211), suggesting thatgam andkil may be analogous to the 4X174 overlap. Asmight be expected for an economic regulatorysystem involving a small number of proteins, theamount of A DNA devoted to regulatory sites isvery small.With all of the evolutionary development ev-

ident in the highly organized, intensively used,and tightly regulated X genome, the "silent" (or"useless") b region remains an embarrassment.Three possible reasons for the existence of sucha silent region are: (i) the proteins coded by thisregion serve a valuable viral function under someset of conditions in which X is not normallystudied in the laboratory (e.g., different hosts,growth medium, etc.); (ii) the DNA itself servesa function (e.g., size or structural aspects ofpackaging); (iii) the silent DNA is useless to thevirus, an evolutionary vestige of a recombina-tional event with another phage or with hostDNA, preserved by the kindness of the friendlymolecular biologist, who has reduced furtherevolutionary pressure to a minimum. Sincephage deleted for most of this silent region cangrow and make phage particles normally, thesecond possibility does not seem tenable, exceptas a special case of the first. We think that thethird possibility has some conceptual merit, inthe sense that molecular biologists often assumethat whatever is, has function.

ACKNOWLEDGMENTSWe thank the community of lambdologists for pro-

viding the information used in constructing the mapand for making lambda research a pleasant as well asfascinating field of endeavor. We thank especially An-drew Becker, Carla Echols, Loretta Hurren, and MickiToban for heroic editorial assistance and Nick Storyfor skillful and patient drafting.

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genetic map of bacteriophagegenetic mapof phage lambda 579 table 1. genesofphageaandtheirfunction...

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