J. Appl. Genet. 43(4), 2002, pp.

403-414

Review article

Structure and evolution of plant disease resistance genes

Przemysaw LEHMANN

Institute of Plant Genetics, Polish Academy of Sciences, Pozna, Poland

Abstract. This article reviews recent advances that shed light on plant disease resis-
tance genes, beginning with a brief overview of their structure, followed by their
genomic organization and evolution. Plant disease resistance genes have been
exhaustively investigated in terms of their structural organization, sequence evolution
and genome distribution. There are probably hundreds of NBS-LRR sequences and
other types of R-gene-like sequences within a typical plant genome. Recent studies re-
vealed positive selection and selective maintenance of variation in plant resistance and
defence-related genes. Plant resistance genes are highly polymorphic and have diverse
recognition specificities. R-genes occur as members of clustered gene families that
have evolved through duplication and diversification. These genes appear to evolve
more rapidly than other regions of the genome, and domains such as the leucine-rich re-
peat, are subject to adaptive selection.

Key words: evolution, gene cluster, leucine-rich repeats, NBS-LRR genes, plant pathogen,
resistance genes, R-genes.

Abbreviations: NBS nucleotide-binding site, LRR leucine-rich repeats, CC

coiled-coil domain, TIR Toll and IL-1 receptor domain, IL-1 interleukin,
KIN ser/thr protein kinase, avr avirulence gene, Pto resistance gene to
Pseudomonas syringae pv. tomato, R resistance, RPP5 resistance gene to
Peronospora parasitica 5, RPS2 resistance gene to Pseudomonas syringae 2,
TMV tobacco mosaic virus, Cf resistance gene to Cladosporium fulvum,
Ka nonsynonymous (amino acid changing) substitution rate,
Ks synonymous (silent) substitution rate, RPP4 resistance gene to
Peronospora parasitica 4, RPM1 resistance gene to Pseudomonas
syringae 1, kb kilobases, ATP adenosine triphosphate, GTP guanosine
triphosphate.

Received: August 21, 2002. Accepted: September 30, 2002.

Correspondence: P. LEHMANN, Institute of Plant Genetics, Polish Academy of Sciences,
ul. Strzeszyska 34, 60-479 Pozna, Poland, e-mail: pleh@igr.poznan.pl
404 P. Lehmann

Introduction

In plants, strong defence responses to invading pathogens often conform to

a gene-for-gene relationship. A resistance to a pathogen is only observed when
the pathogen carries a specific avirulence (avr) gene and the plant carries a corre-
sponding resistance (R) gene (FLOR 1971). Because avr-R gene interactions are
observed in many plant-pathogen systems and are accompanied by a characteris-
tic set of defence responses, a common molecular mechanism underlying avr-R
gene mediated resistance has been postulated. One simple model which explains
the gene-for-gene relationship is that pathogen avr genes generate a specific mo-
lecular signal (elicitor) that is recognized directly or indirectly by cognate recep-
tors encoded by plant R-genes. Recent cloning of plant resistance genes and
corresponding pathogen avirulence genes provided tools for a direct test of
this elicitor-receptor model (HAMMOND-KOSACK, JONES 1997, ELLIS et al. 2000,
DANGL, JONES 2001).
Plant disease resistance genes conferring resistance to the major classes of
plant pathogens, including bacteria, virus, fungi and nematodes, have been iso-
lated from different plant species. Sequence analysis of the predicted proteins of
these cloned disease resistance genes reveals that common motifs occur in resis-
tance genes of diverse origin and pathogen specificity. Five classes of disease re-
sistance genes have been defined according to the structural characteristics of
their predicted protein products. Plant disease resistance often involves the inter-
action of these single, dominant, or semidominant genes in a specific relationship
gene-for-gene. However, the genetic basis of disease resistance is well recog-
nised for a large number of plant-pathogen interactions, the basic problem of how
plant disease resistance genes originate and evolve are the subject of much discus-
sion (SONG et al. 1997, RONALD 1998, STAHL, BISHOP 2000, RICHLY et al.
2002). This paper reviews the structure and evolution of R-genes using informa-
tion from genetic and molecular analysis.

Structure and classification of plant resistance genes

The majority of R-genes encode proteins with specific domains. Most of them
contain a conservative nucleotide-binding site (NBS) which is crucial to the bind-
ing of ATP or GTP (SARASTE et al. 1990). The second key domain is
the leucine-rich region (LRR). This domain is characterized by a protein-protein
interaction. The LRR domain contains a series of repeated motifs of amino acids
with leucine or other hydrophilic amino acid at a regular distance (JONES, JONES
1997, KAJAVA 1998). Both subclasses of NBS-LRR proteins can be differentiated
on the basis of their amino-terminal sequence. One contains the TIR domain with
homology to factor natural resistance Toll and interleukin receptor-like genes
(HAMMOND-KOSACK, JONES 1997), and the other subclass contains a putative
 Structure and evolution of plant disease resistance genes 405

structure coiled coil (CC) (PAN et al. 2000). The class of CC-NBS-LRR genes
contains probably a few subfamilies differing in the size and localization of
the coiled-coil domain (Figure 1). These structures form homo- or het-
ero-oligomeric associations facilitating interactions between proteins and possi-
bly playing a role in the interaction of R-proteins with molecules downstream in
the signal transduction pathway (TORII et al. 1998). Comparative sequence analy-
ses demonstrated that R specificity resides largely in the LRRs, which are under
diversifying selection to increase amino-acid variability in residues thought to be
solvent exposed (PARNISKE et al. 1997).

LRR LRR
Extracellular

cell wall
plasma
membrane
cell wall
Intracellular
KIN TIR CC
KIN
cytoplasm
Cf-2 Pto Xa21 NBS NBS
Cf-4
Cf-5
Cf-9
LRR LRR

N RPS2
L6 RPM1
RPP5

Figure 1. Representation of the location and structure of the five main classes of plant disease
resistance proteins: LRR-leucine-rich repeats; NBS-nucleotide-binding site; KIN-ser/thr
protein kinase; CC-coiled-coil domain; TIR-Toll and interleukin receptor domain.

The NBS-LRR type of genes is abundant in plant species. For example,

in Arabidopsis it is estimated that at least 150 different NBS-LRR genes exist
comprising up to 1% of the genome (MEYERS et al. 1999). The homology between
resistance proteins led to a suggestion that they may function in a conserved path-
way in eukaryotes, which is activated in response to pathogen challenge (BELVIN,
ANDERSON 1996). Genes which encode R proteins of the NBS-LRR type have
been isolated from a number of species and differ significantly in their primary se-
quence, overall length, and the number of their LRR (BENT 1996, JONES, JONES
1997). Based on common molecular features R genes are divided into five classes
(Table 1) (HAMMOND-KOSACK, JONES 1997).
406 P. Lehmann

Table 1. Classification of plant disease resistance genes

Predicted features
Class Gene Plant Pathogen References
of R proteins

1 Hm1 Maize Helmintosporium maydis Detoxifying enzyme JOHAL, BRIGGS

HC-toxin reductase 1992
2 Pto Tomato Pseudomonas syringae Intracellular ser/thr MARTIN et al. 1993
(avrPto) protein kinase

3a RPS2 Arabidopsis Pseudomonas syringae CC/NBS/LRR BENT et al. 1994

(avrRpt2)
RPM1 Arabidopsis Pseudomonas syringae GRANT et al. 1995
(avrRpm1/avrB)

3b N Tobacco Tobacco mosaic virus TIR/NBS/LRR WHITHAM et al.

L6 Flax Melampsora lini 1994
RPP5 Arabidopsis Peronospora parasitica

4 Cf-2 Tomato Cladosporium fulvum Extracellular LRR JONES et al. 1994,

Cf-4 DIXON et al. 1996,
Cf-5 DIXON et al. 1998
Cf-9
5 Xa21 Rice Xanthomonas oryzae Extracellular SONG et al. 1995
LRR/kinase domain

Genomic organization of the main R-genes in higher plants

The Pto gene from tomato encodes a ser/thr protein kinase (KIN) that confers re-
sistance to Pseudomonas syringae carrying the avirulence gene avrPto
(CARLAND, STASKAWICZ 1993, MARTIN et al. 1993). Protein PTO might func-
tion through a phosphorylation cascade, triggered by a direct AVRPTO-PTO in-
teraction (SCOFIELD et al. 1996, TANG et al. 1996). The Pto gene is a member of
a complex locus of five tandemly aligned and closely related genes encoding
ser/thr protein kinase (MICHELMORE, MEYERS 1998). Only one resistance speci-
ficity has been mapped to the Pto locus of tomato. This is in contrast to many other
resistance loci in plants, at which multiple resistance specificities occur either as
allelic variants of a single gene or as paralogous genes at complex loci.
The rice resistance gene Xa21 confers resistance against the bacterial pathogen
Xanthomonas oryzae pv. oryzae. The gene Xa21 is a member of a multigene fam-
ily containing at least eight members (SONG et al. 1995). Most of these members
can be mapped to a single locus on chromosome 11 that is linked to at least nine
major resistance genes and one quantitative trait locus for resistance (RONALD et
al. 1992, SONG et al. 1995). Furthermore, pulsed-field gel electrophoresis analysis
demonstrated that most members of the Xa21 gene family are located in a 230 kb
genomic region (RONALD et al. 1992, WILLIAMS et al. 1996). The Xa21 gene en-
codes a transmembrane receptor carrying a large extracellular LRR domain and
 Structure and evolution of plant disease resistance genes 407

an intracellular protein kinase domain (SONG et al. 1997). The structure suggests
a role of the LRR domain in the cell surface recognition of a pathogen ligand and
the subsequent activation of a kinase leading to a defence response (SONG et al.
1995). Thus, the structure of Xa21 confirms the evolutionary link between differ-
ent classes of plant disease resistance genes. The tomato Cf-x genes which confer
resistance to Cladosporium fulvum encode single pass membrane proteins with
extracellular LRRs (JONES et al. 1994). The Cf genes in tomato are located at two
complex loci. The Cf-9 and Cf-4 genes were mapped to identical locations on
the short arm of chromosome 1, whereas Cf-2 and Cf-5 were mapped at identical
locations on the short arm chromosome 6 (JONES et al. 1993). The flax L locus
confers resistance to strains of the rust fungus Melampsora lini (LAWRENCE et al.
1995). Thirteen active alleles of the flax L gene are known, twelve of which en-
code different flax rust resistance specificities; they are over 90% identical, but
show variation over the entire length of the protein (ELLIS et al. 1999). These al-
leles differ from one another by an average of 40 amino acid replacements in do-
main 2 of the LRR. However, they differ little at synonymous sites, which
indicates that these alleles arose from common ancestral alleles in a relatively re-
cent past (BERGELSON et al. 2001). Sequence variation among these alleles and
transgenic experiments based on them reveal the mutational and recombinational
determinants of their resistance specificity differences (ELLIS et al. 1999).
The RPS2 gene of the Arabidopsis thaliana mediates resistance to strains of
the bacterial pathogen Pseudomonas syringae pv. tomato expressing the avrRpt2
gene (KUNKEL et al. 1993, YU et al. 1993). The predicted RPS2 gene product is
a protein of 909 amino acids that contains several interesting protein domains, in-
cluding a Leu zipper region, a NBS, a small internal hydrophobic domain, and
a series of 14 imperfect LRR (BENT et al. 1994, MINDRINOS et al. 1994). RPS2 be-
longs to a growing class of resistance genes that share a striking amount of struc-
tural and organizational similarity (BENT 1996, HAMMOND-KOSACK, JONES
1997). Seventeen accessions of Arabidopsis thaliana were sequenced to explore
the diversity present in the coding region of the RPS2 locus. An unusually high
level of nucleotide polymorphisms was found (1.26%), with nearly half of the ob-
served polymorphisms resulting in amino acid changes in the RPS2 protein.
Seven alleles were identified. Several of them conferring resistance were found to
be closely related, whereas susceptibility to disease was conferred by widely di-
vergent alleles (CAICEDO et al.1999).

Duplication and recombination as mechanisms of R-genes evolution

Duplication plays a key role in creating complex genetic systems. The most
cloned resistance genes are members of multigene families (see above), indicating
that gene duplication and subsequent diversification are common processes in
plant gene evolution (MARTIN et al. 1993, WHITHAM et al. 1994, LAWRENCE
408 P. Lehmann

et al. 1995). At least two additional clusters of the gene Cf-9 homologues on
the short arm of chromosome 1 of tomato have been found (WIT, JOOSTEN 1999).
Likewise, chromosomal duplications created entirely new clusters of R genes in
lettuce (PARAN et al. 1992). Molecular analysis of the Cf-2/Cf-5 and Cf-4/Cf-9
loci demonstrated that unequal crossing-over and/or gene conversion have played
a fundamental role in their evolution (PARNISKE et al. 1997). The presence of two
similar copies of Cf-2 is most likely the result of a recent sequence duplication,
most probably a result of unequal crossing-over (DIXON et al. 1996). Also Cf-9
and Cf-4 differ by one nucleotide in 1057 bp at their 3 ends and are identical for
a further 5.2 kb downstream (THOMAS et al. 1997). This suggests that one of these
genes was also generated from a recent cross-over or gene conversion event.
Rapid sequence exchange among tandemly repeated gene families generally leads
to sequence homogenization between members. A comparison of intergenic re-
gions at the Cf-4/Cf-9 locus of three haplotypes revealed a high degree of se-
quence rearrangements, whereas in the coding regions a patchwork of sequence
similarities was observed (PARNISKE et al. 1997). The noted variable sequence
patches could result either from successive rounds of reciprocal recombination or
from gene conversion events. In a homozygous background, the Cf-9 gene was
found to be very stable. In contrast, the meiotic stability of Cf-9 was sharply re-
duced in a Cf-4/Cf-9 transheterozygous background.
PARNISKE et al. (1997) proposed that the polymorphism of the intergenic re-
gions suppresses unequal recombination in homozygotes and sister chromatids,
thereby preventing sequence homogenization of the gene family. In this situation,
recombination between regions of high homology within a coding region may ac-
tually contribute to the maintenance of a useful combination of R gene
specificities. In a Cf-4/Cf-9 transheterozygous background, homologous se-
quences aligned unequally are used as recombination templates. Such unequal re-
combination alters the number of gene family members as well as the composition
of the clusters, resulting in increased variation within the population (PARNISKE et
al. 1997). The analysis of the Cf-4/Cf-9 and Cf-2/Cf-5 loci has revealed their dy-
namic nature in a number of different haplotypes (THOMAS et al. 1998). If this
mechanism contributes to the evolution of Cf-genes in natural populations, it pre-
dicts significant levels of haplotype variation within Lycopersicon species
(THOMAS et al. 1998). Duplication and diversification of the Pto gene family led
to the generation of alternative recognition capabilities of the encoded proteins
(MARTIN et al. 1994, ZHOU et al. 1995). Family member FEN carries 87% amino
acid identity to PTO, but confers sensitivity to the insecticide fenthion rather than
resistance to Pseudomonas syringae pv. tomato. Similarly, data from the studies
on the Xa21 family in rice suggest that duplication and subsequent divergence
generated two Xa21 subfamilies, although in this event, a functional role for
the A2 family remains to be determined (SONG et al. 1997). In addition to duplica-
tion events, recombination contributes to the observed diversity of the plant gene
families. For example, recombination at the maize disease resistance locus Rp1
 Structure and evolution of plant disease resistance genes 409

has been observed to be associated with the creation of novel resistance pheno-
types (RICHTER et al. 1995).
Comparative mapping in grasses and Solanaceae suggests that the reorganiza-
tion of NBS-LRR genes can occur rapidly (LEISTER et al. 1998, PAN et al. 2000).
In extreme cases, copy number can vary widely among varieties of a particular
species. Moreover, in different grass species, syntenic loci are frequently lost
(LEISTER et al. 1998), although plant genomes may harbour clusters of highly dis-
similar NBS-LRR genes, the so-called mixed clusters (LEISTER et al. 1998, 1999,
PAN et al. 2000). Both interlocus recombination and divergent selection acting on
duplicated genes have been suggested as major factors in the generation of gene
diversity within existing clusters (LEISTER et al. 1998, PARNISKE, JONES 1999).
Unlike these mechanisms, unequal crossing-over and gene conversion should
cause sequence homogenization, and thus lead to the concerted evolution of
R-genes within clusters (PARNISKE, JONES 1999, YOUNG 2000).

Adaptive selection of LRR domains

The idea that the adaptive evolution of LRR domains allows for a rapid generation
of altered recognition specificities has been confirmed by much evidence.
The characterization of nucleotide substitution patterns in R-gene families has
provided insight on the function and evolution of selected coding domains. Dur-
ing studies on the function of genes, the ratio of nucleotide substitutions that lead
to amino acid replacements (nonsynonymous substitution, Ka) and nucleotide
substitutions that do not exchange amino acids (synonymous substitutions, Ks)
is especially informative. In most protein-coding genes, values of the ration Ka/Ks
is less than 1, this observation is consistent with the functional constraint against
amino acid replacements. However, when the value of ration Ka/Ks is significantly
greater than 1, it provides evidence for a positive selection for amino acid substitu-
tion (STAHL, BISHOP 2000).
Detection of positive selection often depends on considering only those sites
predicted to be important in recognition. Evidence of adaptive selection is rare,
but appears to be most common in gene regions encoding surface antigens of para-
sites or viruses (ENDO et al. 1996). It is expected that fragments of proteins that
bind ligand will be subject to stronger adaptive selection than regions of those pro-
teins that play a structural function. LRR regions of R-genes are receptor domains
for the specific recognition of pathogens elicitors (see this review above) and may
be involved in direct protein-protein interactions. The analysis of Cf gene family
members revealed that the solvent-exposed residues of the LRR domain framed
by aliphatic residues exhibit increased Ka/Ks ratios relatively to other residues in
the LRR domain, suggesting that solvent-exposed residues play a role in ligand
410 P. Lehmann

binding (PARNISKE et al. 1997). Similarly, a comparison of nucleotide substitu-

tions in the LRR coding regions of Xa21 and gene family member Xa21D re-
vealed that, although Xa21 and Xa21D share 99.1% sequence identity,
nonsynonymous substitutions occur significantly more frequently than do synon-
ymous substitutions in the LRR. This above mentioned result is consistent with
the LRRs putative role in ligand binding (WANG et al. 1998). Adaptive selection
has been investigated among R-genes in additional species of plants (lettuce 11,
Arabidopsis 9, 10, tomato 8 and rice 23). Most of them revealed high rates of
amino acid replacement changes in the solvent-exposed residues of the LRR do-
main (STAHL, BISHOP 2000).
These results indicate that the LRR domain, which governs race-specific
pathogen recognition, is subject to adaptive evolution. Diversity at the LRR do-
main would provide an evolutionary advantage for recognizing, binding, and de-
fending against a broad array of pathogens. Adaptive evolution in the LRR is
consistent with an evolutionary arms race in this respect that pathogens should im-
pose selection to continually alter recognition specificity.

Conclusions

The ability of populations of viral, bacterial and fungal pathogens to shift to viru-
lent biotypes is well known in field situations. Thus the ability of plant species to
survive over evolutionary time might depend on their ability to generate useful di-
versity at resistance gene loci. Our understanding of the nature, genome organiza-
tion and evolution of R gene loci has increased immensely in recent years.
Common conclusions in the evolution of R genes and gene families are emerging
on the basis of sequence analysis of cloned R genes. The ancient nature of
NBS-LRR sequences, their separation into distinct lineages and more recent di-
versification helps to explain the observed sequence diversity and structural fea-
tures of this gene family. At a genomic level, extensive gene clusters are a striking
property of most R genes that is probably related to a balance between creating
new specificities and conserving old ones. The well-known mechanisms for gen-
erating diversity of R genes are duplication and recombination. Then a gene fam-
ily is formed by chromosomal duplication and a subsequent divergence of
progenitor sequences. This process creates new loci, changes the number of fam-
ily members, and provides homologous sequences for recombination and unequal
crossing-over events. The recombination at highly conserved regions in intragenic
regions allows for the formation of novel gene combinations. The adaptive evolu-
tion of LRR domains allows for the rapid generation of altered recognition
specificities. Comparisons of the sequences of genes carried in some resistance
gene clusters have provided molecular evidence of these recombination events.
 Structure and evolution of plant disease resistance genes 411

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