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Genetic patterns of plant host-parasite interactions
PERSPECTIVES 24 Rober:son, H.M. (1993)Nature362, 241-245 25 Garcia-Fem~ndez,J., Marfany, G., BagunL J. and Sal6, E. (1993) Nature 364, 109-110 26 Collins,J., Forbes, E. and Anderson, P. (1989) Genetics 121, 47-55 27 Capy, P., Koga, A., David,J.R. and Hard, D.L. (1992) Genetics 130, 499-506 28 Periquet, G., Hamelin, M.H., Bigot, Y. and Lepissier, A. (1989)./. Evol. Biol. 2, 223-229 29 Kaplan, N., Darden, T. and Langley, C.H. (1985) Genetics 109, 459--480 30 Capy, P., David,J.R. and Hard, D.L. (1992) Genet/ca86, 37--46 31 Montchamp--Moreau,C. etal. (1993) Mol. Biol. Evol. 10, 791---803 32 Mamyama,K., School K.D. and Hard, D.L. (1991) Genetics 128, 777-784 33 Sawyer, S.A. etai. (1987) Genetics 115, 51--63 34 Kellner, M., Burmester, A., WOstemeyer,A. and W6stemeyer, J. (1993) Curr. Genet. 23, 334--337 35 Rousset, F., Vautrin, D. and Solignac, M. (1992) Prec. R. $oc. London, Ser. B 247, 163-168 36 Blissard, G.W. and Rohrmann, G.F. (1990) Annu. Rev. Entomol. 35, 127-155 37 Miller, D.W. and Miller, L.K. (1982) Nature 299, 562-564 38 Ashbumer, M. (1989) Drosophila: A Laboratory Handbook, Cold Spring Harbor Laboratory Prc~s
39 Houck, M.A., Clark,J.B., Peterson, K.R. and Kidwell, M.G. (1991) Science 253, 1125-1129 40 Aubert,J. and Solignac, M. (1990) Evolution 44, 1272-1282 41 Bryan, G., Garzza, D. and Hard, D.L. (1990) Genetics 125,
103--114 42 Montchamp-Moreau, C., Periquet, G. and Anxolab6h~re, D. (1991)./. Evol. Biol. 4, 131-140 Bucheton, A., Simonelig, M., Vaury, C. and Crozatier, M. (1986) Nature322, 650--652 44 Periquet, G., Hamelin, M.H., Kalmes, R. and Ecken, J. (1991) Genet. Sel. Evol. 22, 393--402 45 Counce, S.J. (1959) Dros. Inf. Ser. 33, 127-128 46 Brandt-Rosquist,K. and Ltining, K.G. (1984) Hereditas 101, 69-73 47 Palmgren, B. and Lake, S. (1986) Hereditas 105, 155-156 48 Lachaise, D. et al. (1988) Evol. Biol. 22, 159-225 P. CAPY IS IN THE LABORATOIREDE BIOLOGI£~'TGi~NgiII~UE EVOLVHVEg CNRS, 91198 GXF/YW~rE CEDEX, FRANC_Z; D. ANXOI.ABI~HF.RE IS IN THE LABORATOIRE DE DYNAMII~UE
Du GI;NOME~r EVOL~O~ CNRS INS'aIt~ JACI~F.S MONO~ UNZVERSrr~PARIS VI-VII, 75251 PARIS CZDEX05, FP.aNC~ T. LANGIN IS IN THE LABDRATOIRE DE PLASTiCt~ nU G~NOM~ BIODIVERSITi~ ET EVOLUTION DES CHAMPIGNONS~ BA'~I'iMENT
400--U~v~ERSr~ PAroS XI, 91405 OP.SAVCr~F26FRANC.F.
REVIEWS
O n e field of genetics focuses on traits that are not intrinsic to an organism: host-parasite genetics. The host trait of resistance to infection and the parasite trait of infectiousness are controlled by the combined genotypes of host and parasite rather than by either genotype alone. A host's ability to fend off parasites and a parasite's ability to infect can be passed through the germ line. This differs from the adaptive (somatic) genetics of the immune system, in which resistance is acquired during the life of an organism and is not passed on through the gametes; nevertheless, it is interesting to note that both acquired and constitutive resistance may depend upon some of the same mechanisms t. Here, we review the genetics of plant host-parasite interactions and speculate on a conceptual framework for unifying what appear to be disparate systems. Two genetic patterns describe complex plant host-parasite interactions. The first is associated with variability in the parasite's production of, or the host's sensitivity to, compatibility factors. Compatibility factors cause changes in the host's physiology, rendering it susceptible to infection. Resistance that prevents the action of compatibility factors is typically stable, because a gain of function (a new compatibility factor) is required to overcome it. In the absence of such variability, a second pattern, known as the incompatibility or genefor-gene interaction, is observed. This second pattern is associated with variability in the parasite's production of, or the host's sensitivity to, incompatibility or avirulence factors, which change tho host's physiology in such a way as to prevent infection. Resistance based on the action of avirulence factors is typically
Genetic patterns of plant host-parasite interactions STEVEN P. BRIGGSAND GURMUI~ S. JOHAL
A parasite's ability to Iofect and a host's ability to resist Iofection can be heritable traits. Patterns of Inheritance suggest how host genes interact with parasite genes to determine whether or not Iofectton occurs. Rocent progress in the isolation and characterl~atio~ qf these ge,tes in plants sheds new light on parasitisng
unstable, because a loss of function (for example, a mutation of the avirulence gene) can overcome it. Consideration of the two patterns suggests that hosts that do not prevent the action of compatibility factors evolve, as a secondary level of defense, a sensitivity to avirulence factors.
Genetic patterns The genetics of parasitism can be classified as either simple or complex, depending upon the absence (simple) or existence (complex) of multiple races or strains of the parasite. Races are distinguished by altered virulence or altered specificity. Altered specificity is usually manifested in the form of a new race that overcomes the resistance of certain host genotypes. There are two simple patterns: a parasite may be able to attack (1) all members of the host population, or (2) only some members. Because simple patterns of parasitism are found within a subset of parasites that have complex patterns of infection, we focus herein on complex patterns.
TIG JANUARY1994 VOL. 10 NO. 1 U)94F.l~evier,%ienceLtO(I'K) 01£~. 9525/Q4/$0",00
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Races can be classified according to which Host strain AxB subsets of the host population they can infect. A B F2 An example is shown in Fig. 1. A given host 3 1 RA r B r A Re 9 3 strain and parasite race are said to be com/ avr A patible if infection occurs; compatibility is .==. =. ,=., .. + + / Avr B designated by a + sign 2. Race 1 of the parasite Pathogen race can infect host strain A, but not B; in contrast, Avr A ] + 2 race 2 of the parasite is compatible with host avrB -+ -+ I strain B, but not A. Crosses between the host strains reveal that strain A carries a gene RA 9 l D that confers dominant resistance to race 1 of the parasite, while strain B carries a second 3 + gene RB for resistance to race 2. These genes are shown here as being independent, but are (1 x 2) F z in many cases allelic. 3 + Three conclusions can be drawn from this example. First, host resistance to the parasite 1 + + is conditional, since it depends on the genotype of the parasite. The classification of members of the host population as either resistant or susceptible is overly simplistic; FIG. 1. The gene-for-gene interaction. Colonization occurs in compatible (+) given time, new races are almost certain to but not incompatible (-) combinations. F2 progenyfrom the hosts (A X B) or parasites (1 X 2) segregate in a dihybrid ratio, permitting the avr and r appear. genotypes to be assigned. Second, the ability to infect is conditional, since it depends on the genotype of the host. In the example, the ability to infect is a recessive trait the production of compatibility factors, molecules that that is controlled by so-called avirulence genes. The alter the host's physiology so as to allow its colonization by the parasite. The discovery of compatibility concept of avirulence genes seems counterintuitive: why would a parasite have genes that prevent it from factors 6 preceded the elucidation of the associated being compatible? The normal function of parasite genetic pattern, which is known as the compatibility interaction. Many compatibility factors produced by avirulence genes is almost certainly not to prevent infection. By analogy with the immune system, aviru- pathogens have been characterized 7, and compatilence genes may encode 'antigens' that interact with the bility factors from symbionts have recently been described 8--10. The paired boxes in Fig. 2 show that the products of resistance genes, leading to incompatibility. Not only is the concept of avirulence genes counterin- genetic pattern of the incompatibility interaction is the tuitive, the term itself is in conflict with accepted defi- reciprocal of the compatibility interaction. The naturally nitions in phmt pathology: so-called avirulence genes occurring types of parasitism involving muhiple races t';itlse inconq~atibility rather than loss of virulence. Since of a parasite fall into one or other of these two patterns A plant parasite in which both types of intervirulence refers to the degree of damage caused by an infectious strain3, il' tho strain is not infectious then its action are variable has yet to be identified, although we suspect that such cases do exist. virulence cannot be defined. Hence, :t more accurate term fi~r avirulence genes would be 'incompatibility Molecular mechanisms genes'. What are the mechanisms by which plant parasites Third, incompatibility prevails over compatibility, regatxUess of how many compatible genetic combi- gain or are denied ingress by their hosts? The answers to this question are just emerging. The best-undernations there are. "I'lleretbre, incompatibility is the result of positive interactions between host and parasite stood example is seen in the leaf blight and ear mold genes; compatibility occurs in the absence of these of maize caused by race 1 of the fungus Cocbliobohcs interactions. This pattern was discovered by Flor 4 and is carbonum. This disease was first reported in 1938, and frequently referred to as the 'gene-for-gene interaction', genes involved in resistance to it were described soon because a particular gene (or allele) in the parasite afterward II. Scheffer and his associates identified a cominteracts with a particular gene (or allele) in the host to patibility factor that is produced only by race 1, and named this factor, HC-toxin (for Hehninthosporium specify the outcome of infection. However, interaction between host and parasite genes can also resuh in carbonum toxin; Helmintbosporium is the former compatibility, as described below. Because of this genus of the imperfect stage of the fungus). Known ambiguity, we prefer the term 'incompatibility inter- compatibility factom, including those produced by symbionts, are typified by their toxicity at high levels action' to describe the pattern discovered by Flor. in vitro, while structural characterizations revealed that A second complex pattern was discovered by Scheffer et al. 5 This type of interaction differs from the HC-toxin is a cyclic tetrapeptide 1z-to. HC-toxin is one incompatibility (gene-fovgene) interaction in that the of many host-selective toxins that arc-elaborated by plant pathogens; most host-selective toxins appear to parasite's genes act to cause compatibility rather than incompatibility; that is, the genetic determinants of the be compatibility factors, but some are virulence facparasite are compatibility genes, rather than avirulence tors, and are responsible for some or all of the pathological effects of parasitism -~.'r. or incompatibility genes. Compatibility genes control TIG JANUARY1994 VOL. 10 No. 1
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REVIEWS HC-toxin reductase (HCTR), was discovered in extracts from resistant plants 2°, and a combination of genetic I Sapriphyte and biochemical analyses revealed Parasitism traits that HM1 controls the activity of HCTR (e.g., appressorium) (Ref. 21). The mechanism of resistance to infection is therefore inactivation of Non-host Potential parasite the compatibility factor HC-toxin by the HCTR enzyme, and DNA seSensitivity to I I [ compatibility I I I Compatibility factor quence characterization of the cloned factor ~ ~ ~ HM1 gene has shown that this locus encodes HCTR (Ref. 22). Host Parasite Resistance to compatibility factors, "~ and hence to the parasites producing ~.~--~ Compatib;lity I them, can also be conferred by recessive resistance genes. This type of I Yes I Can the compatibility I No , resistance might be explained if the [ ~ Imechanismbe disrupted?l ~ dominant allele encodes a receptor for the compatibility factor; a plant carryPreventactionof J Become hypersensitive ing a recessive allele will therefore lack compatibility factor I to parasite the receptor, and compatibility will be R r , R r prevented. Attempts to test this hyCorn I - I + I Unique i n t e r a c t i o n =l Inc I - I + I Unique interaction = pothesis directly have been made with corn[ I " [c°mpatible I inc [ + I 4= line°raP atible the Vb gene of oats; this locus confers dominant susceptibility to Cochliobolus Resistance STABLE "~ = UNSTABLE victoriae. Wolpert and Macko 23 found that labeled victorin (the compatibility 1~o. 2. Schematic representation of evolution of host-parasite interactions. The genetic factor produced by C. victoriae) bound pattern of the incompatibility(gene-for-gene) interaction is shown in the bottom right to a 100 kDa protein in susceptible box; the compatibility interaction is shown bottom left. The compatibilitythat underlies (Vb), but not resistant (v b), oat plants. the incompatibility interaction is postulated to result from the shaded + combination in However, others found that victorin the compatibility interaction. antibody bound to the same protein in extracts of victorin-treated plants with Two key findings establish HC-toxin as a compatiboth genotypes 24, Thus, further studies are required bility factor: (1) the ability to infect maize and to proto clarify the basis of insensitivity seen in vb plants, duce HC-toxin co-segregate with a single locu#, Nevertheless, it seems plausible that insensitivity to TOX2, and (2) exogenous application of HC-toxin compatibility factors could be caused by loss or along with a non-producing (and non-infectious} iso- modification of their receptors. late of the fungus permits infection tS, These attributes Molecular mechanisms involved in incompatibility demonstrate that HC-toxin is the molecular determi- (gene-for-gene) interactions are also being elucidated; nant that permits C. carbonum race 1 to colonize several incompatibility genes have been characterized maize. In addition, this factor affects only those genoand the products of a few are known7. In some types of maize that are susceptible to race 1, demoninstances, incompatibility genes encode incompatibility strating that it is also the determinant of host genotype factors that rapidly kill the cells of resistant plants. specificity. A complex gene, or collection of genes, has For example, certain races of the tomato pathogen been cloned from the TOX2 locus 16, and Walton and Cladosporium fidw~m produce a protein that is toxic colleagues have proven that TOX2 encodes enzyme(s) only to tomato cultivars that carry the Cf9 resistance that are required for the synthesis of HC-toxin. gene 25,26, In another case, the incompatibility gene The receptor or target for HC-toxin is not known. avrD of Pseudomonas syrlngae pv. tomato appears to Treating susceptible maize with purified HC-toxin stim- encode an enzyme involved in synthesis of a product ulates root growth 17 and enhances protoplast vi- that plays the role of an incompatibility factor27. ability m, among other effects; at high concentrations, Perhaps the death of host cells restricts the growth of ion transport is induced and death eventually ensues 19, parasites, by denying them the water and nutrients Identification of the target for HC-toxin may help clarify they need, or by activating in the surrounding cells the exactly how compatibility is established. production of defense factors, host molecules that disResistance of maize to infection by C. carbonum rupt pathogen physiology. Efforts to identify the correrace 1 is controlled by two nuclear genes: HM1, which sponding incompatibility factors for the majority of maps to chromosome 1 and HM2, which maps to cloned incompatibility genes have failed, and the chrotnosome 9 (Ref. 11). The activity of HM1 can promechanisms by which these genes cause incompativide fully dominant resistance in all organs throughout bility remain a mystery. the life of the plant. HM2 is semi-dominant and its Intensive attempts are being made to isolate host activity increases in effectiveness as the plant reaches resistance genes involved in incompatibility intermaturity; seedlings that have the gene are susceptible actions. Martin et aL28 have cloned the Pro gene that to infection. An enzyme that inactivates HC-toxin, confers resistance against Ps. syringae pv. tomato; TIG JANUARY1994 VOL. 10 No. 1
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the sequence of the gene suggests that it encodes a serine/threonine protein kinase. This finding, supports the notion that a signal transduction mechanism is required for the expression of resistance.
host population is uniformly sensitive to the compatibility factor, resistance may depend upon a hypersensitivity to parasite incompatibility gene products.
Stabk resistance Integration of the compatibility and gene-for-gene concepts Incompatibility interactions are superimposed on a basic compatibility between the host and parasite ~-. What is the basis of this compatibility? One possibility is simply that pathogens are not sensed by the host: compatibility would then be a passive consequence of the absence of avirulence factors. Contrary to this 'avoidance' hypothesis, we speculate that all parasites produce compatibility factors. The list of compatibility factors known to be produced by parasites of plants 7 and animals 29-33 is growing. A lack of genetic variance for either production of, or sensitivity to, compatibility factors could explain the basic compatibility that underlies incompatibility (gene-for-gene) interactions. Loss of the ability to produce a compatibility factor would be lethal for an obligate parasite, as would loss of host sensitivity to the factor. This may explain why such variance has never been reported in gene-for-gene diseases, which were traditionally studied using obligate parasites. More complex patterns are predicted, in which a given parasite specializes first into pathovars that infect particular host species (or genera) and then into races that infect only certain genotypes of a host species. Such patterns could be the result of compatibility factors that determine host-species range (based on host sensitivity to the compatibility factors) and avirulence genes that specify genotype susceptibility within a host species. The taxonomic level at which host-range determinants act can be narrow or broad3'~. Our hypothetical example is meant only to illustrate that compatibility factors establish the potential host range, whereas incompatibility factors, when present, establish the actual host range. Our concept of the relationship between compatibility and incompatibility interactions is presented in an evolutionary context (Fig, 2), For a parasite to evolve from a saprophyte that lives off decaying organic matter, it must acquire the ability to penetrate, grow and reproduce on a host. Some adaptations may be simple, while others may be more complex. Most fungal parasites can produce appressoria, specialized infection structures that anchor the hyphae over the site of penetration; saprophytes do not produce such structures. The actual host range of a potential parasite is determined by the molecular signals it exchanges with its host. The primary level of interaction involves the establishment of a compatible relationship. Two things are required: the parasite must produce a compatibility factor, and the host must be sensitive to that factor. Races of the parasite may be distinguished by whether they produce the compatibility factor. Host strains may vary in their sensitivity to the factor and, hence, in their susceptibility to the parasite. Sensitivity can be controlled by variance in the host target for the compatibility factor (for example, elimination or modification of the target) or by inactivation of the compatibility factor by the host. In cases where the
Several predictions of our model can be tested. Let us consider the most important prediction. Resistance to parasites based on insensitivity to compatibility factors should be more stable over time and across parasite populations than gene-for-gene resistance, because whereas the first requires a gain of function in the parasite to overcome the resistance (that is, production of a new compatibility factor), the second type of resistance can be overcome by a loss of function in the parasite (that is, loss of an incompatibility gene). However, it may not always be feasible for the parasite to lose this function, particularly if the incompatibility gene is required for fitness; stable resistance based on just such a case has indeed been observed35. With depressing consistency, gene-forgene resistance lasts only a few years; in contrast, the resistance of oats to C. victoriae has been stable for 50 years. Resistance of maize to C. carbonum race 1 w ~ not overcome until the 1970s, when race 3 of the pathogen was first observed; race 3, although much less virulent than race 1, produces a novel compatibility factor 36. In conclusion, it therefore seems that an increased emphasis on understanding the basis of compatibility may be the most effective strategy for identifying and engineering stable resistance to parasites.
Acknowledgements We thank W. Beavis and N. Yalpani for helpful comments,
References I 2 3 4 5
Gaffney, T. et aL (1993) Science 261,754-756 Eilingboe, A.H. (1976) Pbyslol. Plant Pathol. 4. 761-778 Yoder, O.C. (1980) Annu. Rev. Phytopatbol. 18, 103-129 Fior, H.H. (1956) Adv. Genet. 8, 29-54 Scheffer, R.P., Nelson, R.R, and Uilstmp, A.J. (1967) PbytopatboloID, 57, 1288-1291 6 Tanaka, S. (1933) Mere. Coll. Agr. Kyoto Univ. 28, 1-31 7 Briggs, S.P. and Johal, G.S. in Molecular-Genetic Analysis of Plato Metabolism and Development (Puigdomenech, P. and Coruzzi, G., eds), Springer-Verlag(in press) 8 Truchet, G. etal. (1991) Nature351, 670-.673 9 Spaink, H.P. etal. (1991) Nature354, 125-130 10 Roche, P. etal. (1991) Ceil67, 1131-1143 11 Nelson, O.E. and Ullstrup, A.J. (1964)J. Hered. 55, 19%199 12 Walton, J.D., Earle. E.D. and Gibson, B.W. (1982) Biocbem. Btopbys. Res, Commun. 107, 78%794 13 Liesch,J.M. et al. (1982) Tetrahedron 38, 45--48 14 Gross, M.L. et al. (1982) Tetrabedron Lett. 23, 5381-5384 15 Comstock, J.C. and Scheffer, R.P. (1973) PhytopatholoRF 63, 24--29 16 Panaccione, D.G., Scoff-Craig.J.S., Pocard, J. and Walton. J.D. (1992) Proc. Natl Acad. Sci. USA 89, 6590-6594 17 Kuo, M., Yoder, O.C. and ScheffeL R.P. (1970) Phytopathology60, 36%368 18 Wolf, S.J. and Eade, E.D. (1991) Plant Sci. 70, 127-137 /9 Yodel O.C. and Scheffer, R.P. (1973) Plant Physiol. 52, 518-523 20 Meeley, R.B. and Walton. J.D. ( 1991) Plant Physiol. 97. 1080-1086 21 Meeley, R.B.,Johal. G.S., Briggs. S.P. and Walton, J.D. (1992) Plant Cell 4, 71-77
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31 Sodeinde, O.A. et al. (1992) Science 258, 1004-1007 32 Bielecki,J., Youngman, P., Connelly, P. and Portnoy, D.A. (1990) Nature 345, 17%176 33 Arruda, S. et al. (1993) Science261; 1454--1457 34 Keen, N.T. (1990) Annu. Rev. Genet. 24, 447--463 35 Keamey, B. and Staskawicz, B.J. (1990) Nature 346,
391-418 26 van Kan, J.A.L., van den Ackerveken, G.F.J.M. and de Wit, P.J.G.M. (1991) Mol. PlantMicrob. Interact. 4, 52-59 27 Keen, N.T. et al. (1990) Mol. Plant Microb. Interact. 3, 112-121 28 Martin, G.B. et al. Science (in press) 29 Galyov, E.E., Ha!~ansson, S., Forsberg, A. and Wolf-Watz, H. (1993) Nature 361,730-732 30 Breton, C.B. et ai. (1992) Proc. Natl Acad. Sci. USA 89. 9647-9651
38%386 36 Xiao,J., Tsuge, T. and Doke, N. (1992) Physiol. Mol. Plant Patbol. 40, 359-370 S.P. BRIGGS IS IN THE 1DEPARTMENT OF BIOTECHNOLOGY RESEARCa, PIONEER HI-RUED INTERNATIONAL, JOHNSION,
IA 50131, USA, AND G.S. JOHAL IS IN THE DEPARTMENT OF AGRONOMY, UNIVERSITY OF MISSOURI, COLUMBIA,
MO 65211, USA.
What do BMPsdo in mammals? Clues from the mouse short-earmutation
T h e vertebrate skeleton has an incredible variety of shapes, sizes and arrays of repeating elements that have long fascinated developmental biologists and comparative anatomists. Until recently, little was known about the molecular signals that control skeletal morphogenesis, how these signals act and how they vary in organisms with different morphological DAVID M. KINGSLEY traits. During the past five years a remarkable family of secreted molecules has been found, and members of Bone morphogenetic proteins (BMPs) are a family of this family are strong candidates for the signals that secreted signaling molecules that were originally Isolated induce the formation of bone and cartilage during on the basis of their remarkable ability to induce the embryonic development. These molecules have been formation of ectopic bones when implanted into adult variously called osteogenins, osteogenic proteins, dpp- animals, Theflrst mutations tdent~led in a mammaUan Vgl-related (DVR) factors t and bone morphogenetic BMPgene suggest that members of this family induce the proteinsa (BMPs), the term used het~h.. BMPs itt'e formation, p a t t e m l q and repair o f particular found in adult bones, and were originally purified on morpholo&ical features in higher anhnals, the basis of their ability to induce local formation of ectopic bone anti cartilage when implanted under The signaling regitm, of BMPs is strikirtgly con. the skin or into the mr, sole of rats. Implants con- served in evoluticm, and closely related proteins are taining BMPs induce a complex cascade of chemot:txis, present in X e n o p u s and Drosophila. BMP-Iik¢ proproliferation and cellular differentiation that closely re- teins have thus existed for at least a half billion years, sembles the normal process of embryonic bone forma- and must pre-date the evolutionary ,emergence of tion3. Great interest is now focused on these proteins bone and cartilage. Mutations in a BMP-like gene in because of their remarkable ability to induce new Drosophila disrupt dorsal-ventral axis formation and bone and cartilage and their potential clinical appli- are lethal. These findings, and the expression of cations in stimulating repair of bone fractures a. If these nmmmalian BMPs in many different tissues (Table 1 ), molecules are natural osteoinductive signals in higher suggest that BMPs may also play diverse roles in animals, many general questions about skeletal form Mgher animals t. and patterning, evolutionary variation in body form One way to test the functions of these genes in and skeletal diseases may eventually be framed as vertebrates is to examine the phenotypes associated detaded questions about the expression of, and cellu- with mutations in different BMP genes. We recently lar response to, different members of the BMP family. found that one of the eight known BMP genes is Although BMPs induce bone and cartilage when defective in mice carrying mutations at the short-ear implanted in animals, their normal physiological func- (se) locusS; this locus has i'~een studied for more tions have not yet been firmly established. Cloning than 70 years because of its interesting effects on studies (Table 1) have shown that most BMPs belong the formation and repair of skeletal elements. The to a large family of secreted signaling molecules that phenotypes of short-ear mice provide strong genetic are structurally related to transforming growth factor evidence that specific BMPs are essential for the develbeta l,a (TGF-[~). Members of this family are syn- opment of particular morphological features in higher thesized as larger precursor proteins with an amino- animals. terminal signal sequence, a propeptide region and a mature carboxy terminus of 110-140 amino acids. Skeletal defects in short.ear mice The mature protein forms homo- or heterodimers that The original se mutation was found in pet mice from represent the active signaling molecule 4. the Lathrop mouse ram1 in Massachusetts6. The mutation TIG JANtJARY 1994 VOL. 10 No. 1 ( Itl)-I El,crier ~ienve LId ~1:K)()1¢~1 - t):,2~ 9-1 $(~-.1~)
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39 Houck, M.A., Clark,J.B., Peterson, K.R. and Kidwell, M.G. (1991) Science 253, 1125-1129 40 Aubert,J. and Solignac, M. (1990) Evolution 44, 1272-1282 41 Bryan, G., Garzza, D. and Hard, D.L. (1990) Genetics 125,
103--114 42 Montchamp-Moreau, C., Periquet, G. and Anxolab6h~re, D. (1991)./. Evol. Biol. 4, 131-140 Bucheton, A., Simonelig, M., Vaury, C. and Crozatier, M. (1986) Nature322, 650--652 44 Periquet, G., Hamelin, M.H., Kalmes, R. and Ecken, J. (1991) Genet. Sel. Evol. 22, 393--402 45 Counce, S.J. (1959) Dros. Inf. Ser. 33, 127-128 46 Brandt-Rosquist,K. and Ltining, K.G. (1984) Hereditas 101, 69-73 47 Palmgren, B. and Lake, S. (1986) Hereditas 105, 155-156 48 Lachaise, D. et al. (1988) Evol. Biol. 22, 159-225 P. CAPY IS IN THE LABORATOIREDE BIOLOGI£~'TGi~NgiII~UE EVOLVHVEg CNRS, 91198 GXF/YW~rE CEDEX, FRANC_Z; D. ANXOI.ABI~HF.RE IS IN THE LABORATOIRE DE DYNAMII~UE
Du GI;NOME~r EVOL~O~ CNRS INS'aIt~ JACI~F.S MONO~ UNZVERSrr~PARIS VI-VII, 75251 PARIS CZDEX05, FP.aNC~ T. LANGIN IS IN THE LABDRATOIRE DE PLASTiCt~ nU G~NOM~ BIODIVERSITi~ ET EVOLUTION DES CHAMPIGNONS~ BA'~I'iMENT
400--U~v~ERSr~ PAroS XI, 91405 OP.SAVCr~F26FRANC.F.
REVIEWS
O n e field of genetics focuses on traits that are not intrinsic to an organism: host-parasite genetics. The host trait of resistance to infection and the parasite trait of infectiousness are controlled by the combined genotypes of host and parasite rather than by either genotype alone. A host's ability to fend off parasites and a parasite's ability to infect can be passed through the germ line. This differs from the adaptive (somatic) genetics of the immune system, in which resistance is acquired during the life of an organism and is not passed on through the gametes; nevertheless, it is interesting to note that both acquired and constitutive resistance may depend upon some of the same mechanisms t. Here, we review the genetics of plant host-parasite interactions and speculate on a conceptual framework for unifying what appear to be disparate systems. Two genetic patterns describe complex plant host-parasite interactions. The first is associated with variability in the parasite's production of, or the host's sensitivity to, compatibility factors. Compatibility factors cause changes in the host's physiology, rendering it susceptible to infection. Resistance that prevents the action of compatibility factors is typically stable, because a gain of function (a new compatibility factor) is required to overcome it. In the absence of such variability, a second pattern, known as the incompatibility or genefor-gene interaction, is observed. This second pattern is associated with variability in the parasite's production of, or the host's sensitivity to, incompatibility or avirulence factors, which change tho host's physiology in such a way as to prevent infection. Resistance based on the action of avirulence factors is typically
Genetic patterns of plant host-parasite interactions STEVEN P. BRIGGSAND GURMUI~ S. JOHAL
A parasite's ability to Iofect and a host's ability to resist Iofection can be heritable traits. Patterns of Inheritance suggest how host genes interact with parasite genes to determine whether or not Iofectton occurs. Rocent progress in the isolation and characterl~atio~ qf these ge,tes in plants sheds new light on parasitisng
unstable, because a loss of function (for example, a mutation of the avirulence gene) can overcome it. Consideration of the two patterns suggests that hosts that do not prevent the action of compatibility factors evolve, as a secondary level of defense, a sensitivity to avirulence factors.
Genetic patterns The genetics of parasitism can be classified as either simple or complex, depending upon the absence (simple) or existence (complex) of multiple races or strains of the parasite. Races are distinguished by altered virulence or altered specificity. Altered specificity is usually manifested in the form of a new race that overcomes the resistance of certain host genotypes. There are two simple patterns: a parasite may be able to attack (1) all members of the host population, or (2) only some members. Because simple patterns of parasitism are found within a subset of parasites that have complex patterns of infection, we focus herein on complex patterns.
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Races can be classified according to which Host strain AxB subsets of the host population they can infect. A B F2 An example is shown in Fig. 1. A given host 3 1 RA r B r A Re 9 3 strain and parasite race are said to be com/ avr A patible if infection occurs; compatibility is .==. =. ,=., .. + + / Avr B designated by a + sign 2. Race 1 of the parasite Pathogen race can infect host strain A, but not B; in contrast, Avr A ] + 2 race 2 of the parasite is compatible with host avrB -+ -+ I strain B, but not A. Crosses between the host strains reveal that strain A carries a gene RA 9 l D that confers dominant resistance to race 1 of the parasite, while strain B carries a second 3 + gene RB for resistance to race 2. These genes are shown here as being independent, but are (1 x 2) F z in many cases allelic. 3 + Three conclusions can be drawn from this example. First, host resistance to the parasite 1 + + is conditional, since it depends on the genotype of the parasite. The classification of members of the host population as either resistant or susceptible is overly simplistic; FIG. 1. The gene-for-gene interaction. Colonization occurs in compatible (+) given time, new races are almost certain to but not incompatible (-) combinations. F2 progenyfrom the hosts (A X B) or parasites (1 X 2) segregate in a dihybrid ratio, permitting the avr and r appear. genotypes to be assigned. Second, the ability to infect is conditional, since it depends on the genotype of the host. In the example, the ability to infect is a recessive trait the production of compatibility factors, molecules that that is controlled by so-called avirulence genes. The alter the host's physiology so as to allow its colonization by the parasite. The discovery of compatibility concept of avirulence genes seems counterintuitive: why would a parasite have genes that prevent it from factors 6 preceded the elucidation of the associated being compatible? The normal function of parasite genetic pattern, which is known as the compatibility interaction. Many compatibility factors produced by avirulence genes is almost certainly not to prevent infection. By analogy with the immune system, aviru- pathogens have been characterized 7, and compatilence genes may encode 'antigens' that interact with the bility factors from symbionts have recently been described 8--10. The paired boxes in Fig. 2 show that the products of resistance genes, leading to incompatibility. Not only is the concept of avirulence genes counterin- genetic pattern of the incompatibility interaction is the tuitive, the term itself is in conflict with accepted defi- reciprocal of the compatibility interaction. The naturally nitions in phmt pathology: so-called avirulence genes occurring types of parasitism involving muhiple races t';itlse inconq~atibility rather than loss of virulence. Since of a parasite fall into one or other of these two patterns A plant parasite in which both types of intervirulence refers to the degree of damage caused by an infectious strain3, il' tho strain is not infectious then its action are variable has yet to be identified, although we suspect that such cases do exist. virulence cannot be defined. Hence, :t more accurate term fi~r avirulence genes would be 'incompatibility Molecular mechanisms genes'. What are the mechanisms by which plant parasites Third, incompatibility prevails over compatibility, regatxUess of how many compatible genetic combi- gain or are denied ingress by their hosts? The answers to this question are just emerging. The best-undernations there are. "I'lleretbre, incompatibility is the result of positive interactions between host and parasite stood example is seen in the leaf blight and ear mold genes; compatibility occurs in the absence of these of maize caused by race 1 of the fungus Cocbliobohcs interactions. This pattern was discovered by Flor 4 and is carbonum. This disease was first reported in 1938, and frequently referred to as the 'gene-for-gene interaction', genes involved in resistance to it were described soon because a particular gene (or allele) in the parasite afterward II. Scheffer and his associates identified a cominteracts with a particular gene (or allele) in the host to patibility factor that is produced only by race 1, and named this factor, HC-toxin (for Hehninthosporium specify the outcome of infection. However, interaction between host and parasite genes can also resuh in carbonum toxin; Helmintbosporium is the former compatibility, as described below. Because of this genus of the imperfect stage of the fungus). Known ambiguity, we prefer the term 'incompatibility inter- compatibility factom, including those produced by symbionts, are typified by their toxicity at high levels action' to describe the pattern discovered by Flor. in vitro, while structural characterizations revealed that A second complex pattern was discovered by Scheffer et al. 5 This type of interaction differs from the HC-toxin is a cyclic tetrapeptide 1z-to. HC-toxin is one incompatibility (gene-fovgene) interaction in that the of many host-selective toxins that arc-elaborated by plant pathogens; most host-selective toxins appear to parasite's genes act to cause compatibility rather than incompatibility; that is, the genetic determinants of the be compatibility factors, but some are virulence facparasite are compatibility genes, rather than avirulence tors, and are responsible for some or all of the pathological effects of parasitism -~.'r. or incompatibility genes. Compatibility genes control TIG JANUARY1994 VOL. 10 No. 1
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REVIEWS HC-toxin reductase (HCTR), was discovered in extracts from resistant plants 2°, and a combination of genetic I Sapriphyte and biochemical analyses revealed Parasitism traits that HM1 controls the activity of HCTR (e.g., appressorium) (Ref. 21). The mechanism of resistance to infection is therefore inactivation of Non-host Potential parasite the compatibility factor HC-toxin by the HCTR enzyme, and DNA seSensitivity to I I [ compatibility I I I Compatibility factor quence characterization of the cloned factor ~ ~ ~ HM1 gene has shown that this locus encodes HCTR (Ref. 22). Host Parasite Resistance to compatibility factors, "~ and hence to the parasites producing ~.~--~ Compatib;lity I them, can also be conferred by recessive resistance genes. This type of I Yes I Can the compatibility I No , resistance might be explained if the [ ~ Imechanismbe disrupted?l ~ dominant allele encodes a receptor for the compatibility factor; a plant carryPreventactionof J Become hypersensitive ing a recessive allele will therefore lack compatibility factor I to parasite the receptor, and compatibility will be R r , R r prevented. Attempts to test this hyCorn I - I + I Unique i n t e r a c t i o n =l Inc I - I + I Unique interaction = pothesis directly have been made with corn[ I " [c°mpatible I inc [ + I 4= line°raP atible the Vb gene of oats; this locus confers dominant susceptibility to Cochliobolus Resistance STABLE "~ = UNSTABLE victoriae. Wolpert and Macko 23 found that labeled victorin (the compatibility 1~o. 2. Schematic representation of evolution of host-parasite interactions. The genetic factor produced by C. victoriae) bound pattern of the incompatibility(gene-for-gene) interaction is shown in the bottom right to a 100 kDa protein in susceptible box; the compatibility interaction is shown bottom left. The compatibilitythat underlies (Vb), but not resistant (v b), oat plants. the incompatibility interaction is postulated to result from the shaded + combination in However, others found that victorin the compatibility interaction. antibody bound to the same protein in extracts of victorin-treated plants with Two key findings establish HC-toxin as a compatiboth genotypes 24, Thus, further studies are required bility factor: (1) the ability to infect maize and to proto clarify the basis of insensitivity seen in vb plants, duce HC-toxin co-segregate with a single locu#, Nevertheless, it seems plausible that insensitivity to TOX2, and (2) exogenous application of HC-toxin compatibility factors could be caused by loss or along with a non-producing (and non-infectious} iso- modification of their receptors. late of the fungus permits infection tS, These attributes Molecular mechanisms involved in incompatibility demonstrate that HC-toxin is the molecular determi- (gene-for-gene) interactions are also being elucidated; nant that permits C. carbonum race 1 to colonize several incompatibility genes have been characterized maize. In addition, this factor affects only those genoand the products of a few are known7. In some types of maize that are susceptible to race 1, demoninstances, incompatibility genes encode incompatibility strating that it is also the determinant of host genotype factors that rapidly kill the cells of resistant plants. specificity. A complex gene, or collection of genes, has For example, certain races of the tomato pathogen been cloned from the TOX2 locus 16, and Walton and Cladosporium fidw~m produce a protein that is toxic colleagues have proven that TOX2 encodes enzyme(s) only to tomato cultivars that carry the Cf9 resistance that are required for the synthesis of HC-toxin. gene 25,26, In another case, the incompatibility gene The receptor or target for HC-toxin is not known. avrD of Pseudomonas syrlngae pv. tomato appears to Treating susceptible maize with purified HC-toxin stim- encode an enzyme involved in synthesis of a product ulates root growth 17 and enhances protoplast vi- that plays the role of an incompatibility factor27. ability m, among other effects; at high concentrations, Perhaps the death of host cells restricts the growth of ion transport is induced and death eventually ensues 19, parasites, by denying them the water and nutrients Identification of the target for HC-toxin may help clarify they need, or by activating in the surrounding cells the exactly how compatibility is established. production of defense factors, host molecules that disResistance of maize to infection by C. carbonum rupt pathogen physiology. Efforts to identify the correrace 1 is controlled by two nuclear genes: HM1, which sponding incompatibility factors for the majority of maps to chromosome 1 and HM2, which maps to cloned incompatibility genes have failed, and the chrotnosome 9 (Ref. 11). The activity of HM1 can promechanisms by which these genes cause incompativide fully dominant resistance in all organs throughout bility remain a mystery. the life of the plant. HM2 is semi-dominant and its Intensive attempts are being made to isolate host activity increases in effectiveness as the plant reaches resistance genes involved in incompatibility intermaturity; seedlings that have the gene are susceptible actions. Martin et aL28 have cloned the Pro gene that to infection. An enzyme that inactivates HC-toxin, confers resistance against Ps. syringae pv. tomato; TIG JANUARY1994 VOL. 10 No. 1
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the sequence of the gene suggests that it encodes a serine/threonine protein kinase. This finding, supports the notion that a signal transduction mechanism is required for the expression of resistance.
host population is uniformly sensitive to the compatibility factor, resistance may depend upon a hypersensitivity to parasite incompatibility gene products.
Stabk resistance Integration of the compatibility and gene-for-gene concepts Incompatibility interactions are superimposed on a basic compatibility between the host and parasite ~-. What is the basis of this compatibility? One possibility is simply that pathogens are not sensed by the host: compatibility would then be a passive consequence of the absence of avirulence factors. Contrary to this 'avoidance' hypothesis, we speculate that all parasites produce compatibility factors. The list of compatibility factors known to be produced by parasites of plants 7 and animals 29-33 is growing. A lack of genetic variance for either production of, or sensitivity to, compatibility factors could explain the basic compatibility that underlies incompatibility (gene-for-gene) interactions. Loss of the ability to produce a compatibility factor would be lethal for an obligate parasite, as would loss of host sensitivity to the factor. This may explain why such variance has never been reported in gene-for-gene diseases, which were traditionally studied using obligate parasites. More complex patterns are predicted, in which a given parasite specializes first into pathovars that infect particular host species (or genera) and then into races that infect only certain genotypes of a host species. Such patterns could be the result of compatibility factors that determine host-species range (based on host sensitivity to the compatibility factors) and avirulence genes that specify genotype susceptibility within a host species. The taxonomic level at which host-range determinants act can be narrow or broad3'~. Our hypothetical example is meant only to illustrate that compatibility factors establish the potential host range, whereas incompatibility factors, when present, establish the actual host range. Our concept of the relationship between compatibility and incompatibility interactions is presented in an evolutionary context (Fig, 2), For a parasite to evolve from a saprophyte that lives off decaying organic matter, it must acquire the ability to penetrate, grow and reproduce on a host. Some adaptations may be simple, while others may be more complex. Most fungal parasites can produce appressoria, specialized infection structures that anchor the hyphae over the site of penetration; saprophytes do not produce such structures. The actual host range of a potential parasite is determined by the molecular signals it exchanges with its host. The primary level of interaction involves the establishment of a compatible relationship. Two things are required: the parasite must produce a compatibility factor, and the host must be sensitive to that factor. Races of the parasite may be distinguished by whether they produce the compatibility factor. Host strains may vary in their sensitivity to the factor and, hence, in their susceptibility to the parasite. Sensitivity can be controlled by variance in the host target for the compatibility factor (for example, elimination or modification of the target) or by inactivation of the compatibility factor by the host. In cases where the
Several predictions of our model can be tested. Let us consider the most important prediction. Resistance to parasites based on insensitivity to compatibility factors should be more stable over time and across parasite populations than gene-for-gene resistance, because whereas the first requires a gain of function in the parasite to overcome the resistance (that is, production of a new compatibility factor), the second type of resistance can be overcome by a loss of function in the parasite (that is, loss of an incompatibility gene). However, it may not always be feasible for the parasite to lose this function, particularly if the incompatibility gene is required for fitness; stable resistance based on just such a case has indeed been observed35. With depressing consistency, gene-forgene resistance lasts only a few years; in contrast, the resistance of oats to C. victoriae has been stable for 50 years. Resistance of maize to C. carbonum race 1 w ~ not overcome until the 1970s, when race 3 of the pathogen was first observed; race 3, although much less virulent than race 1, produces a novel compatibility factor 36. In conclusion, it therefore seems that an increased emphasis on understanding the basis of compatibility may be the most effective strategy for identifying and engineering stable resistance to parasites.
Acknowledgements We thank W. Beavis and N. Yalpani for helpful comments,
References I 2 3 4 5
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38%386 36 Xiao,J., Tsuge, T. and Doke, N. (1992) Physiol. Mol. Plant Patbol. 40, 359-370 S.P. BRIGGS IS IN THE 1DEPARTMENT OF BIOTECHNOLOGY RESEARCa, PIONEER HI-RUED INTERNATIONAL, JOHNSION,
IA 50131, USA, AND G.S. JOHAL IS IN THE DEPARTMENT OF AGRONOMY, UNIVERSITY OF MISSOURI, COLUMBIA,
MO 65211, USA.
What do BMPsdo in mammals? Clues from the mouse short-earmutation
T h e vertebrate skeleton has an incredible variety of shapes, sizes and arrays of repeating elements that have long fascinated developmental biologists and comparative anatomists. Until recently, little was known about the molecular signals that control skeletal morphogenesis, how these signals act and how they vary in organisms with different morphological DAVID M. KINGSLEY traits. During the past five years a remarkable family of secreted molecules has been found, and members of Bone morphogenetic proteins (BMPs) are a family of this family are strong candidates for the signals that secreted signaling molecules that were originally Isolated induce the formation of bone and cartilage during on the basis of their remarkable ability to induce the embryonic development. These molecules have been formation of ectopic bones when implanted into adult variously called osteogenins, osteogenic proteins, dpp- animals, Theflrst mutations tdent~led in a mammaUan Vgl-related (DVR) factors t and bone morphogenetic BMPgene suggest that members of this family induce the proteinsa (BMPs), the term used het~h.. BMPs itt'e formation, p a t t e m l q and repair o f particular found in adult bones, and were originally purified on morpholo&ical features in higher anhnals, the basis of their ability to induce local formation of ectopic bone anti cartilage when implanted under The signaling regitm, of BMPs is strikirtgly con. the skin or into the mr, sole of rats. Implants con- served in evoluticm, and closely related proteins are taining BMPs induce a complex cascade of chemot:txis, present in X e n o p u s and Drosophila. BMP-Iik¢ proproliferation and cellular differentiation that closely re- teins have thus existed for at least a half billion years, sembles the normal process of embryonic bone forma- and must pre-date the evolutionary ,emergence of tion3. Great interest is now focused on these proteins bone and cartilage. Mutations in a BMP-like gene in because of their remarkable ability to induce new Drosophila disrupt dorsal-ventral axis formation and bone and cartilage and their potential clinical appli- are lethal. These findings, and the expression of cations in stimulating repair of bone fractures a. If these nmmmalian BMPs in many different tissues (Table 1 ), molecules are natural osteoinductive signals in higher suggest that BMPs may also play diverse roles in animals, many general questions about skeletal form Mgher animals t. and patterning, evolutionary variation in body form One way to test the functions of these genes in and skeletal diseases may eventually be framed as vertebrates is to examine the phenotypes associated detaded questions about the expression of, and cellu- with mutations in different BMP genes. We recently lar response to, different members of the BMP family. found that one of the eight known BMP genes is Although BMPs induce bone and cartilage when defective in mice carrying mutations at the short-ear implanted in animals, their normal physiological func- (se) locusS; this locus has i'~een studied for more tions have not yet been firmly established. Cloning than 70 years because of its interesting effects on studies (Table 1) have shown that most BMPs belong the formation and repair of skeletal elements. The to a large family of secreted signaling molecules that phenotypes of short-ear mice provide strong genetic are structurally related to transforming growth factor evidence that specific BMPs are essential for the develbeta l,a (TGF-[~). Members of this family are syn- opment of particular morphological features in higher thesized as larger precursor proteins with an amino- animals. terminal signal sequence, a propeptide region and a mature carboxy terminus of 110-140 amino acids. Skeletal defects in short.ear mice The mature protein forms homo- or heterodimers that The original se mutation was found in pet mice from represent the active signaling molecule 4. the Lathrop mouse ram1 in Massachusetts6. The mutation TIG JANtJARY 1994 VOL. 10 No. 1 ( Itl)-I El,crier ~ienve LId ~1:K)()1¢~1 - t):,2~ 9-1 $(~-.1~)
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