Comparative Genetics of Disease Resistance Within the Solanaceae

Corresponding author: Molly Jahn, 312 Bradfield Hall, Cornell University, Ithaca, NY 14853., mmk9{at}cornell.edu (E-mail)

Communicating editor: J. A. BIRCHLER

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Genomic positions of phenotypically defined disease resistance genes (R genes) and R gene homologues were analyzed in three solanaceous crop genera, Lycopersicon (tomato), Solanum (potato), and Capsicum (pepper). R genes occurred at corresponding positions in two or more genomes more frequently than expected by chance; however, in only two cases, both involving Phytophthora spp., did genes at corresponding positions have specificity for closely related pathogen taxa. In contrast, resistances to Globodera spp., potato virus Y, tobacco mosaic virus, and tomato spotted wilt virus were mapped in two or more genera and did not occur in corresponding positions. Without exception, pepper homologues of the cloned R genes Sw-5, N, Pto, Prf, and I2 were found in syntenous positions in other solanaceous genomes and in some cases also mapped to additional positions near phenotypically defined solanaceous R genes. This detailed analysis and synthesis of all available data for solanaceous R genes suggests a working hypothesis regarding the evolution of R genes. Specifically, while the taxonomic specificity of host R genes may be evolving rapidly, general functions of R alleles (e.g., initiation of resistance response) may be conserved at homologous loci in related plant genera.

PLANT disease resistance genes (R genes) are an agriculturally important class of genes that are increasingly well characterized at the molecular level; however, fundamental questions regarding their mechanisms of action and their evolution remain. While remarkable conservation of gene order and function has been observed for genes that govern morphological and physiological traits in many plant families (reviewed in GALE and DEVOS 1998 ), the structural and functional correspondence of R genes has yet to be examined systematically across plant genera. If R genes follow the patterns of conservation observed for other types of plant genes, loci conferring resistance to identical or related pathogens should be found at corresponding positions in genomes of related host taxa. However, if the molecular changes occurring at R loci throughout divergence of genera drastically alter taxonomic specificity but not overall function, the orthologous R genes should occur at corresponding positions in related taxa, although alleles at these loci may be involved in recognizing very different pathogens. Another alternative is that R genes may evolve so rapidly that no conservation of sequence or function will be apparent across genera.

Within an individual plant species, clustering of genes that confer resistance to unrelated pathogens is well documented (POLZIN et al. 1994 ; WITSENBOER et al. 1995 ; DE JONG et al. 1997 ; ASHFIELD et al. 1998 ; SPEULMAN et al. 1998 ), and detailed molecular analyses at several R loci have revealed complex loci consisting of tightly linked R gene homologues (MARTIN et al. 1994 ; DIXON et al. 1996 ; PARNISKE et al. 1997 ; SIMONS et al. 1998 ; THOMAS et al. 1998 ; WILLIAMSON 1998 ). Between sexually compatible species, the pathogen strain specificity and the number of R gene homologues at a given locus have been shown to vary (THOMAS et al. 1998 ). Little is known about the variation in structure and function of orthologous R loci in different genera. One approach to examine this question depends upon domains shared among cloned R genes. These similarities have allowed structurally related sequences, termed R gene analogues (RGAs), to be isolated from many host species (KANAZIN et al. 1996 ; LEISTER et al. 1996 , LEISTER et al. 1998 ; Y. G. YU et al. 1996 ; AARTS et al. 1998 ; SEAH et al. 1998 ; SHEN et al. 1998 ; RIVKIN et al. 1999 ). RGAs are found in abundance in plant genomes, comprising an estimated 2% of the Arabidopsis genome (MICHELMORE and MEYERS 1998 ). In a comparative study in the Gramineae, LEISTER et al. 1998 observed significant variation in RGA copy number and position and found that specific RGA classes usually do not map to similar positions in different genera or even in closely related species. Although this experiment is not informative about conservation of R gene function, it suggests that there is limited conservation of genomic position for R-gene-like sequences, which contrasts with results obtained for other types of plant genes. Whether phenotypically defined R genes exhibit a similar lack of conservation, as proposed by LEISTER et al. 1998 , remains to be seen.

Since genome mapping in the Solanaceae was last reviewed (PILLEN et al. 1996 ), a more complete pepper map has been constructed, allowing comparisons of the three major solanaceous crop genera, Lycopersicon (tomato), Solanum (potato), and Capsicum (pepper) (LIVINGSTONE et al. 1999 ). Many single genes and quantitative trait loci (QTL) that confer resistance to all major classes of plant pathogens (virus, bacteria, nematode, fungus, and insect) have been mapped and/or cloned from solanaceous species (PILLEN et al. 1996 ). Further, a number of pathogens infect broadly within the Solanaceae, allowing direct comparison of genes conferring resistance to the same pathogen in different hosts.

In this study, we present a comparative analysis of genomic organization of solanaceous R genes and R gene homologues to examine the degree to which structure and/or function is conserved in related genomes. The term "R gene" refers to phenotypically defined single genes or quantitative resistance loci (QRL) that function to confer disease resistance to a particular pathogen, for which sequence information may or may not be available. "R gene homologues" are sequences with a close evolutionary relationship to R genes, as determined by a high percentage of sequence similarity, with no implication of related function. The first part of our analysis was restricted to phenotypically defined R genes for which positions on the pepper, tomato, or potato comparative maps have been obtained. For the second part of the analysis, a Southern hybridization-based approach was used to identify and map pepper homologues of cloned solanaceous R genes.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Consensus map construction:
The comparative maps used in this analysis were based on the following populations: tomato, (Lycopersicon esculentum x L. pennellii) F₂, 1276 cM, >1000 loci (PILLEN et al. 1996 ); potato, (Solanum tuberosum x S. berthaultii) x S. berthaultii, 684 cM, >183 loci (TANKSLEY et al. 1992 ); pepper, (Capsicum annuum x C. chinense) F₂, 1246 cM, >1000 loci (LIVINGSTONE et al. 1999 ). Additional potato maps were examined (BONIERBALE et al. 1988 ; GEBHARDT et al. 1991 ), and positions of R loci were inferred from references in Table 1. The tomato-potato and tomato-pepper alignments, based upon common restriction fragment length polymorphism (RFLP) order, have been previously published (TANKSLEY et al. 1992 ; LIVINGSTONE et al. 1999 ). Similar to results from the Gramineae, ~20% of loci in both pepper and tomato did not occur in strict colinear order within homeologous segments (BENNETZEN et al. 1998 ; LIVINGSTONE et al. 1999 ); nevertheless, colinearity within homeologous regions was assumed as a reasonable approximation.

Cross-generic resistance gene clusters:
All published chromosomal locations for R genes and major QRL (LOD > 2 or P < 0.01) for tomato, potato, and pepper were placed on the comparative map (Table 1; Fig 1). In Fig 1, phenotypically defined R genes were placed on a circular diagram showing their positions in host genomes and the chromosomal rearrangements between the three genera. Ninety-three R loci are listed in Table 1 with original references. For clarity, some loci were named or renamed for ease of display. Most positions were inferred from linkage to reference markers and should be considered a best approximation. Comparisons of maps across genera and the use of different mapping population structures and sizes yields an unknown degree of error in estimation of genetic distance; however, as a reasonable approximation, genetic distances were treated as constant across all molecular maps. Cross-generic gene clusters were defined by the presence of two or more genes in distinct genera within 15 cM. This interval was selected to be conservative in light of the observation of MICHELMORE and MEYERS 1998 that intrageneric R gene clusters vary in size from 0 to 30 cM and to remain informative given the inherent imprecision of comparative mapping. The clusters identified are shown in Table 2, and the RFLP markers associated with each cluster were described by TANKSLEY et al. 1992 (TG, tomato random genomic DNA; CD, tomato whole-leaf cDNA; CT, tomato leaf epidermal cDNA) and GEBHARDT et al. 1989 (GP, size-selected potato genomic DNA). Nine genes were placed on the map but excluded from analyses because of imprecise localization or an unclear relationship between comparative maps in a given region (potato loci Gro1, GroVI, and Pi1; tomato loci Ph-1 and Ph-3; pepper QRL phyt2 and pepper loci Pvr4, Pvr7, and Me3). Other mapped loci, such as QRL conferring resistance to cucumber mosaic virus (CMV) in pepper (CARANTA et al. 1997A ) and the recessive pepper veinal mottle virus resistance gene pvr6 (CARANTA et al. 1997B ), could not be assigned a definitive position in comparative maps due to a lack of common markers or a lack of shared marker order between mapping studies. Solanaceous homologues of cloned solanaceous R genes (discussed below) were also included in Fig 1 and Table 1, but were not included when defining R gene clusters.

View larger version (45K): In this window In a new window Download PPT slide   Figure 1. Resistance gene organization in the Solanaceae. The tomato genome is represented by the outer circle, proceeding clockwise from top to bottom of each chromosome. The potato and pepper genomes are represented by the middle and inner circles, respectively. Inversions that distinguish the three genomes are indicated by arrows within the rearranged portions of the potato and pepper maps. Solid lines indicate breaks between chromosomes, and dashed lines indicate the borders of rearranged regions. The five translocations between the pepper and tomato genomes are shown by splitting each of pepper chromosomes 3, 5, 9, 11, and 12 into two halves, each half syntenous to different tomato chromosomes. Resistance genes are designated by solid type; resistance gene homologues are designated by the letter H in outlined type followed by the gene name in subscript. Dark bars along the length of the chromosome are used to denote regions of a chromosome associated with a gene if imprecisely located; names of genes excluded from analyses due to imprecise location are underlined. Ovals are drawn around cross-generic and intrageneric R gene clusters (15 cM) identified by this analysis. Note that genomes are not drawn to scale.

Mapping disease resistance loci in pepper:
Tsw confers resistance to tomato spotted wilt virus (TSWV) in pepper and a single map position was obtained in our interspecific mapping population (JAHN et al. 2000 ). Four CMV QRL that were detected in multiple environments were identified in an intraspecific C. annuum `Maor' x `Perennial' population and placed upon our comparative map by proximity to common RFLP markers (I. PARAN, unpublished results). For these loci, tentatively named cmv11.1, cmv2.1, cmv3.1, and cmv3.2, CMV resistance was evaluated quantitatively over several environments, and linked loci were determined by regression of marker genotypes on CMV resistance. cmv11.1 had a significant effect on resistance on its own (P < 0.0001), while cmv2.1 had a significant effect on resistance only when present in conjunction with cmv11.1 (P < 0.01). cmv3.1 and 3.2 also interacted in multiple environments to produce a significant effect on resistance (P < 0.001). Map positions for Pvr4 and Pvr7, tightly linked potyvirus resistance genes, were obtained by analyzing DNA samples from our interspecific mapping population for a Pvr4-linked sequence characterized amplified region marker tightly linked to Pvr4 (CARANTA et al. 1999 ; GRUBE et al. 2000 ).

Mapping disease resistance gene homologues in pepper:
The clone SL8 (nucleotides 2837–4014 of the tomato disease resistance gene I2C-1) was provided by R. Fluhr (Weizmann Institute of Science, Rehovot, Israel). The full-length cDNA clones of Cf-9 and N were provided by J. D. G. Jones (John Innes Centre, Norwich, United Kingdom) and B. Baker (University of California, Berkeley, CA), respectively. The full-length cDNA clones of Pto and Fen genes were provided by G. Martin and the Sw-5 cDNA was used for RFLP analysis with our pepper mapping filters by S. D. Tanksley (Cornell University, Ithaca, NY). Hybridization of orthologous probes and mapping were performed as previously described (LIVINGSTONE et al. 1999 ); a significance level of LOD > 2.0 was used to assign map positions of R gene homologues.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

R genes and R gene clusters occur at corresponding genomic locations across plant genera:
In total, 12 R gene clusters spanned two or more genera (Fig 1; Table 2). Representative RFLP markers are given for each cluster in Table 2. Tomato-potato clusters are found on T6, T9, T10, and T12; tomato-pepper clusters were found on T1 and T7; and a single pepper-potato cluster exists on T8. Finally, there are 5 gene clusters that involve all three solanaceous genera, located on T3, T4, T9, and T11. These 12 clusters plus 6 additional clusters that occur in only one genus were distributed throughout the genomes. Over half (48/84) of the genes included in this analysis were located within 15 cM of positions of R genes in other genera. Only 14 R genes did not occur in any R gene cluster.

To test the hypothesis that this degree of clustering across genera would be observed by chance, we assumed that within each crop genus, each R gene or intrageneric R gene cluster was independent and occupied a single genomic position. Each of the 12 chromosomes was then divided into five equal 15- to 20-cM portions. Out of 60 possible positions in each genome, R genes/gene clusters occupied 25, 15, and 12 positions in tomato, potato, and pepper, respectively. Assuming random placement, the probability that genes/gene clusters from all three genera would co-occur within corresponding genome segments was calculated as a two-stage problem. First, Y represented the number of times that genes/gene clusters from any two genera (e.g., tomato, potato) are found in corresponding positions. Y is distributed according to the hypergeometric probability distribution (LARSEN and MARX 1986 ) and the probabilities of obtaining all possible values of Y were calculated for the above parameters. The probability that clusters from the third genus correspond with clusters from the other two genera is dependent upon the value of Y and is calculated in the same way. The combined probability that R genes/gene clusters are found in corresponding positions five or more times in the three host genera, as observed, is 0.0028. This is a rough approximation that does not reflect the nonrandom distribution of functional genes in plant genomes; however, the positions of R gene/gene clusters in tomato, potato, and pepper are unlikely to be independent.

R gene inheritance and taxonomic specificity at corresponding positions across plant genera:
Recessive genes, dominant genes, and QRL were all found to occur in cross-generic R gene clusters. Our data set contained only six mapped recessive genes, three of which were found in one cross-generic cluster that contained no dominant genes. The other three recessive genes were not part of any R gene clusters. Of the remaining cross-generic clusters, three contained QRL only, two contained dominant genes only, and six contained a mixture of dominant genes and QRL.

Most cross-generic clusters (10/12) included R genes that control pathogens from two or more major pathogen groupings (e.g., fungi, nematodes, etc.; Fig 1). R genes from different host genera that confer resistance to the same major pathogen group occurred at corresponding positions less frequently (in 6/12 clusters). For example, three virus resistance genes, one for resistance to tomato yellow leaf curl virus in tomato, one for tobacco mosaic virus (TMV) in pepper, and a CMV QRL in pepper, are linked to TG36 (LEFEVBRE et al. 1995; HANSON et al. 2000 ; I. PARAN, unpublished results). Similarly, the potato potexvirus R gene Nx_phu is linked to TG424, which is 12 cM from the tospovirus R gene Sw-5 on T9 and a cucumovirus QRL on pepper chromosome 3 (STEVENS et al. 1995 ; BROMMENSCHENKEL and TANKSLEY 1997 ; TOMMISKA et al. 1998 ; I. PARAN, unpublished results). Finally, potato and pepper alleles conferring resistance to the pathogenic oomycete Phytophthora were found in positions corresponding to tomato genes conferring resistance to the true fungal pathogens Oidium, Stemphylium, Cladosporium, Fusarium, Verticillium, and Alternaria on T3, T4, T6, and T9 (BEHARE et al. 1991 ; DICKINSON et al. 1993 ; BALINT-KURTI et al. 1994 ; VAN DER BEEK et al. 1994 ; VAN DER BIEZEN et al. 1995 ; LEFEBVRE and PALLOIX 1996 ; VAKALOUNAKIS et al. 1997 ; LI et al. 1998 ; OBERHAGEMANN et al. 1999 ).

In only two cases, both involving Phytophthora species, genes for resistance to the same pathogen genus were found in corresponding genomic locations in different host genera. In pepper, a QRL (phyt3) for resistance to Phytophthora capsici is associated with TG104 (P < 0.005; LEFEBVRE and PALLOIX 1996 ), which is located 6 cM from TG105 on T11 (PILLEN et al. 1996 ). In potato, R3, R6, and R7 for resistance to P. infestans are tightly linked to GP250 and GP185 (EL-KHARBOTLY et al. 1994 , EL-KHARBOTLY et al. 1996 ), which in turn are tightly linked to TG105 (HAMALAINEN et al. 1997 ). A potato Phytophthora QRL (phyt7) is also located in this region (OBERHAGEMANN et al. 1999 ). A second P. capsici QRL (phyt1) in pepper is associated with TG483, which was reported to be unlinked to any pepper linkage group (LEFEBVRE and PALLOIX 1996 ). On our pepper map, TG483 is located on Capsicum chromosome 5, syntenous to its location on T4. In potato, R2 was localized to a region of T4 spanning TG483 (LI et al. 1998 ), and, although imprecisely mapped, the potato QRL Pi1 was also located in this region (LEONARDS-SCHIPPERS et al. 1994 ). The three mapped P. infestans R genes from tomato, Ph-1, Ph-2, and Ph-3, were unlinked and did not correspond to any of the positions identified in potato or pepper for Phytophthora resistance (PIERCE 1971 ; MOREAU et al. 1998 ).

Comparative mapping of R genes with similar taxonomic specificity across plant genera:
If R gene specificity is conserved across genera, genes conferring resistance to closely related or identical pathogens should be found in corresponding positions in related genera. For several pathogen genera or species, R genes have been mapped in more than one solanaceous genus, thereby allowing a test of this assertion. Pathogens that infect more than one host genus include TMV, TSWV, potato virus Y (PVY), Globodera, Meloidogyne, and Phytophthora species. A total of 38 genes conferring resistance to these pathogens have been mapped in two or more host genera, and only 7 of these were found in regions corresponding to R genes with similar taxonomic specificity in another genus. Of these 7 genes (all Phytophthora genes mentioned above), 4 potato major genes and QRL and one pepper QRL were found in one location, and the remaining pepper and potato QRL were found in a second position.

Six mapped PVY R loci in pepper that occur at four unlinked positions failed to correspond to the position of two linked PVY R loci in potato. Similarly, none of seven Globodera R genes in six unlinked positions in potato corresponded to the single Globodera R gene mapped in tomato. A similar lack of correspondence was observed for TMV R loci (one in tobacco, two in tomato, one in pepper), TSWV R loci (one in pepper, one in tomato; JAHN et al. 2000 ), and loci conferring resistance to Meloidogyne species (one in pepper, one in potato, two in tomato). A fourth Meloidogyne R gene, the pepper gene Me3, was excluded from our analysis because a precise comparative map position could not be ascertained; however, the interval to which Me3 can be definitively assigned corresponds to the position for Mi-3 in tomato, which confers resistance to the same strain of M. incognita (DIJAN-CAPORALINO et al. 1998 ).

To examine more closely the organization and relationship between R loci with similar taxonomic specificity in related hosts, we selected a pathogen, TMV, that infects across host species and for which a cloned solanaceous R gene was available (WHITHAM et al. 1994 ). Resistance to TMV is controlled by the genes N in tobacco (HOLMES 1938 ), Tm-1 (LEVESQUE et al. 1990 ) and Tm-2 (YOUNG et al. 1988 ) in tomato, and L in pepper (LEFEBVRE et al. 1995 ). We used the tobacco N full-length cDNA to identify homologues in pepper by hybridization. Although several (>6) fragments were detected, all five polymorphic fragments mapped to only two chromosomal locations. Both locations were on the short arm of the pepper chromosome corresponding to T11, one ~5 cM distal to CP58 and the other ~30 cM distal from the first. In tobacco, a family of related sequences cluster at the N locus, which is linked to CP58, with additional related sequences linked at an unspecified distance (WHITHAM et al. 1994 ); thus the two positions mapped in pepper may be orthologous to the tobacco loci. These two positions obtained for N homologues in pepper did not correspond to any of the known positions of phenotypically similar TMV R genes in tomato or pepper (see Fig 1). Similarly, in tomato, no N-related sequences have been mapped to regions containing Tm-1 or Tm-2 (OHMORI et al. 1998 ).

While the N homologues in pepper did not cosegregate with any phenotypic resistances mapped to date in pepper or tomato, including resistance to TMV, the position of one homologue coincided precisely with the position of potato loci for potyvirus resistance (Ry_adg/Ry_sto and Ra_adg), Meloidogyne nematode resistance (Rmci), and Synchytrium resistance (Sen1), as well as potato homologues of N (LEISTER et al. 1996 ; HEHL et al. 1999 ). Although these results suggest that Tm-1, Tm-2, and L may not be homologous to the functional N allele from tobacco, N homologues in these genera may be related to other phenotypically defined R genes or may represent as yet undescribed TMV resistance loci. We have also obtained similar results with genes for dominant necrotic localizing resistance to TSWV in tomato and pepper (JAHN et al. 2000 ). Pepper homologues of the tomato gene Sw-5 did not map near the pepper gene Tsw, although they mapped to positions very close to other potato and tomato R genes (see Fig 1 and below).

Comparative mapping of resistance gene homologues:
To examine the correspondence between genomic positions of R gene homologues and known R genes in other species more comprehensively, homologues of five cloned R genes were mapped in pepper. Our results, information from collaborators, and published information are compiled in Fig 1. Pepper homologues of N were found in positions corresponding to the potato Ry_sto/Ry_adg, Rmci, and Sen1, as presented above. Pepper homologues of Sw-5 were found in two positions, one of which corresponded to tomato Sw-5, potato Nx_phu, and the pepper QRL cmv3.1 on T9 (JAHN et al. 2000 ). An additional Sw-5 homologue was found near the tomato QRL Cm7.1 on T7. The high percentage of sequence similarity between Pto and Fen (LOH and MARTIN 1995 ) resulted in identical patterns of hybridization using either sequence as radiolabeled probe under our conditions. Five genomic regions, each containing one or more pepper Pto/Fen homologues, were also clearly identified in pepper. One Pto/Fen homologue and two polymorphic fragments hybridizing to Prf corresponded exactly to the position of Pto, Fen, and Prf in tomato, as well as a Pto homologue in potato (LEISTER et al. 1996 ). The other locations of Pto/Fen homologues are shown in Fig 1: the top of T5 near TG432, corresponding to a large R gene cluster in potato (Grp1, phyt3, Gpa, Pi01, R1, Rx-2, Nb); the top of T6 near TG178, corresponding to a large R gene cluster in tomato (Cm6.1, Mi, Ty-1, Ol-1, Cf-2, Cf-5); and on T9 and T12, where no known Pto/Fen homologues exist in tomato and no mapped R genes occur in any species. One to four additional fragments hybridizing to Prf were identified but were monomorphic in pepper and therefore could not be mapped. The precise number of Prf homologues in the pepper genome and whether they are associated with the additional Pto/Fen homologues found throughout the genome (suggesting duplication of the entire regions surrounding Pto in tomato) remain unknown. Pepper homologues of I2C were also detected in regions corresponding to their positions in the genus of their origin (ORI et al. 1997 ; SIMONS et al. 1998 ). As with Sw-5, Prf, and N, several additional monomorphic fragments hybridizing to I2C were also detected but could not be mapped. Cf-9 homologues were also abundant in pepper, although none could be mapped due to a complete lack of polymorphism for all identified fragments in our pepper mapping populations.

In summary, pepper homologues of all R genes examined (N, Sw-5, Pto, Prf, and I2C) were detected in regions syntenous to their positions on the genus of origin, as expected given the degree of conservation of order of random cDNA and genomic clones between genera. In some cases, additional unique positions of homologues were identified either in the genus of origin or in related genera. While in several cases a homologue of one gene corresponded precisely to the position of phenotypic resistance to a different pathogen in another host, in no case have we identified an R gene whose homologue cosegregates with resistance of similar pathogen specificity in another genus.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

This is the first comprehensive examination of the genomic organization of a wide array of R genes in more than two host genera. This analysis has revealed several cross-generic R gene clusters, suggesting that the chromosomal locations of R genes may be quite broadly conserved through speciation. This trend may be similar to the conservation of genomic position and function that has been observed for several other major categories of plant genes (VAN DEYNZE et al. 1995 ; LEE 1996 ; OSBORN et al. 1997 ; GALE and DEVOS 1998 ) and contrasts with previous hypotheses about the behavior of R loci through evolution (LEISTER et al. 1998 ). The apparent contrast between our findings and those of LEISTER et al. 1998 may be a result of our focus on phenotypically defined R genes conferring resistance to a wide array of pathogens, as opposed to sequence-defined classes of RGAs with unknown function. More limited studies and unpublished results from the Gramineae and Leguminoseae are consistent with the results of the present study. In maize and oat, two rust resistance loci (giving resistance to the pathogens Puccinia sorghi and P. coronata) and resistances to powdery mildew and wheat streak mosaic virus occur on homeologous linkage blocks, although they may be separated by 30 cM or more (G. X. YU et al. 1996 ). Similarly, a cyst nematode R gene in soybean is located in a position corresponding to an anthracnose R gene in common bean (P. GEPTS, personal communication).

One potential use of comparative mapping is the rapid identification of genes similar to those already mapped in related genera. The success of this approach for identification of R genes will require not only that the positions of R loci are conserved across genera, but also that alleles at these loci maintain similar function and specificity for the same or related pathogen taxa. Although 12 cross-generic R gene clusters were identified, R genes with specificity for the same pathogen genus (Phytophthora) occurred only twice at corresponding positions in different host genera, Solanum and Capsicum. Although not definitive, Melodogyne R genes from Capsicum and Lycopersicon may also be located in corresponding map positions (DIJAN-CAPORALINO et al. 1998 ). In contrast, genes conferring resistance to Globodera, TMV, TSWV, and PVY have also been mapped in two or more solanaceous genera and thus far have not been identified in corresponding regions. While absolute conclusions cannot be made because an exhaustive analysis of all R genes that exist in these three genera is not possible, our results suggest two testable hypotheses. The first possibility is that alleles at orthologous loci in different plant genera are nonfunctional or do not typically confer resistance to the same or closely related pathogens. An alternative is that orthologous genes usually do confer resistance to related pathogens. This could be reconciled with our observations if each host genus has an array of R genes targeting a given pathogen or pathogen family, and the subset of genes mapped thus far in different genera by chance are not orthologous. Resolution of these questions will require detailed sequence and functional comparison at loci clearly established to be orthologous. In either case, results from the present study highlight the potential difficulties of using a direct comparative approach to identify similar R genes in related plant genera.

In several (6/12) of the cross-generic clusters identified, genes conferring resistance to the same major pathogen group (e.g., virus, nematode, fungus, bacteria) were found in corresponding positions. Whether the occurrence of these genes in similar locations reflects shared biology or components involved in plant-pathogen interactions remains to be seen. Due to the imprecision of comparative mapping, positional correspondence does not necessarily imply homology. Further examination of these loci, however, may reveal that small changes in nucleotide sequence have given rise to homologues or orthologues with radically different pathogen specificity. Emerging evidence suggests that minimal changes in R gene sequence can slightly alter taxonomic specificity, resulting in the recognition of different pathogen strains or pathotypes (THOMAS et al. 1998 ; WANG et al. 1998 ; ELLIS et al. 1999 ). Relatively small changes in sequence may also result in radical shifts in specificity, especially if avirulence molecules from very different pathogens are structurally similar (BENDAHMANE et al. 1999 ; ROUPPE VAN DER VOORT et al. 1999 ; VAN DER VOSSEN et al. 1999 ). An extreme example is the single gene Mi, which gives resistance to a nematode and an aphid (ROSSI et al. 1998 ; WILLIAMSON 1999 ). This could also account for positional correspondence of R genes for pathogens with no apparent taxonomic relationship, e.g., the possible correspondence between the two unlinked Phytophthora resistance loci in tomato and two Globodera resistance alleles in potato, and the correspondence of two unlinked PVY QRL in pepper with two tomato QRL conferring resistance to Clavibacter michiganensis.

For two pathogens, an R gene had been cloned from a solanaceous genus, providing an additional molecular tool to examine the relationship between resistance alleles from different genera (WHITHAM et al. 1994 ; S. D. TANKSLEY, A. FRARY and S. H. BROMMENSHENKEL, unpublished results). Pepper homologues of N and Sw-5, similar to pepper homologues of other solanaceous R genes, were found in positions corresponding to N and Sw-5 in tobacco and tomato, respectively, as well as in additional positions (JAHN et al. 2000 ). N and Sw-5 homologues were not, however, found in positions corresponding to TMV or TSWV resistance loci in other genera. Comparative mapping results therefore suggest that resistance to the same viral pathogen is controlled by nonhomologous genes in different genera, although this approach is limited by our inability to definitively map all homologues due to lack of polymorphism. Additional information about mutations in the viral genomes that overcome different R genes (WATANABE et al. 1987 ; MESHI et al. 1988 , MESHI et al. 1989 ; PADGETT and BEACHY 1993 ) also suggest that TMV and TSWV resistances appear to be controlled by nonhomologous loci in different solanaceous genera. Nonhomologous R genes may trigger the same conserved response cascade, which would reconcile the phenotypic similarity of the resistance response observed in distinct genera with the apparent lack of a genetic relationship between these loci (INNES 1998 ). To our knowledge, only one case has been reported in which homologous genes at corresponding positions (putative orthologues) confer resistance to identical pathogens in closely related host genera. MULTANI et al. 1998 have shown that orthologues of the maize loci Hm-1 and Hm-2, which confer resistance to Cochliobolus carbonum, exist in corresponding positions and appear to function, giving nonhost resistance to C. carbonum in sorghum and rice. It may be important to note that these genes produce a detoxifying enzyme, which is a fundamentally different host response than is thought to be involved in typical "gene-for-gene" interactions. Putative orthologues with similar pathogen specificity, if identified in the Solanaceae, might represent critical genes that have been under constant selection pressure throughout host divergence. A potentially significant observation from this study is the co-occurrence of an R gene homologue in one species with phenotypic resistance of different pathogen specificity in another. The next step will be to determine the relationship between the sequences of R gene homologues (e.g., N, Sw-5) and the functional R genes in close proximity (e.g., Ry_sto/Ry_adg, Ra_adg, Rmci, Sen1, cmv3.1, Nx_phu). If genes conferring resistance to different pathogens in related hosts are homologous, this suggests that the general function of R genes may be conserved, although taxonomic specificity has changed during host speciation.

Dominant, recessive, and quantitatively inherited genes were all found in cross-generic clusters, in proportions similar to their frequency in the overall data set. It is striking that all three recessive loci that occurred in cross-generic clusters were in the same cluster, which did not contain any dominant genes. This is consistent with the hypothesis that recessive and dominant R genes will be unrelated mechanistically or evolutionarily. Also consistent with this hypothesis is the observation that the recessive barley powdery mildew R gene mlo bears no structural similarity to other cloned R genes (BUSCHGES et al. 1997 ). Further analysis as more recessive R genes are mapped and cloned will shed light on these possibilities.

A majority of cross-generic R gene clusters, including four of the five clusters that comprise genes from all three host genera, were located in close proximity to the end of a chromosome or to a division between conserved linkage blocks. This may be meaningful in light of observations correlating the presence of transposable elements with both large-scale genomic rearrangements (ROBBINS et al. 1989 ; KIM et al. 1998 ) and disease resistance gene clusters (MEYERS et al. 1998 ; SONG et al. 1998 ). Transposable elements may play a role in the creation and maintenance of these clusters and perhaps even in shifts of specificity that may become apparent as we examine the content of these positions through speciation (MEYERS et al. 1998 ; MICHELMORE and MEYERS 1998 ).

In conclusion, this study has revealed limited positional correspondence of phenotypically defined genes conferring resistance to related or identical pathogens across three solanaceous genera. There were two notable exceptions: a pair of unlinked genomic regions contained both resistance to P. infestans in potato and P. capsici in pepper, in addition to the possible correspondence of Me3 and Mi-3. This analysis also revealed unexpected positional correspondence of genes conferring resistance to apparently unrelated pathogens. For example, tomato P. infestans R loci and potato Globodera resistance loci were twice found in roughly corresponding positions, as were tomato Clavibacter QRL and potato PVY QRL. Further, pepper homologues of cloned R genes (e.g., N, Sw-5) were found in positions corresponding with phenotypically defined solanaceous genes that confer resistance to unrelated pathogens, as also seen by HEHL et al. 1999 . While we cannot exclude the possibility that the observed correspondence across genera is coincidental, these pairings suggest intriguing hypotheses about the evolutionary relationships between R genes with apparently unrelated specificities that may be tested easily as sequence information from cloned R genes continues to accrue. Trends emerging from studies in this and other plant families should allow both the definition and resolution of the processes and patterns that govern the function and evolution of this important class of plant genes.

	ACKNOWLEDGMENTS

The authors thank K. D. Livingstone, V. K. Lackney, J. P. Jantz, C. Lewis, A. Frary, and R. Silady for their technical assistance and S. D. Tanksley, B. Baker, R. Fluhr, C. Gebhardt, and B. Staskawicz for generously providing experimental materials and/or unpublished results. We also thank N. Young, G. Martin, W. Frye, L. Landry, A. Matern, and M. Cadle for review of this manuscript. This work was supported in part by U.S. Department of Agriculture National Research Initiative Competitive Grants Program Award Nos. 91-37300-6564 and 94-37300-0333, U.S.-Israel Binational Agricultural Research and Development Award IS-2389-94, and the California Pepper Improvement Foundation/California Pepper Commission. R.C.G. was supported by a Department of Energy/National Science Foundation/United States Department of Agriculture grant to the Research Training Group in Molecular Mechanisms of Plant Processes and gifts from Seminis Vegetable Seeds, Novartis, M. Lavallard, and C. M. Werly.

Manuscript received December 7, 1999; Accepted for publication February 21, 2000.

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