Information on the molecular basis of resistance and the evolution of resistance is crucial to an understanding of the appearance, spread, and distribution of resistance genes and of the mechanisms of host adaptation in natural populations. One potential important genetic constraint for the evolution of resistance is fitness cost associated with resistance. To determine whether host resistance to parasite infection is associated with fitness costs, we conducted simultaneous quantitative trait loci (QTL) mapping of resistance to parasite infection and fitness traits using the red flour beetle (Tribolium castaneum) and the tapeworm parasite (Hymenolepis diminuta) system in two independent segregating populations. A genome-wide QTL scan using amplified fragment length polymorphism (AFLP) markers revealed three QTL for beetle resistance to tapeworm infection. These three QTL account for 44–58% variance in beetle infection intensity. We identified five QTL for fecundity and five QTL for egg-to-adult viability, which accounted for 36–57% and 36–49%, respectively, of the phenotypic variance in fecundity and egg-to-adult viability. The three QTL conferring resistance were colocalized with the QTL affecting beetle fitness. The genome regions that contain the QTL for parasite resistance explained the majority of the variance in fecundity and egg-to-adult viability in the mapping populations. Colocalization of QTL conferring resistance to parasite infection and beetle fitness may result from the pleiotropic effects of the resistance genes on host fitness or from tight linkages between resistance genes and adverse deleterious mutations. Therefore, our results provide evidence that the genome regions conferring resistance to tapeworm infection are partially responsible for fitness costs in the resistant beetle populations.

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PARASITES are intimately dependent on the host for survival, live at the expense of the host, and have deleterious effects on host survivorship and reproductive success. Thus, parasites are important selective agents on hosts. Parasites have been invoked as causal agents in the maintenance of sex (JAENIKE 1978; BREMERMANN 1980; HAMILTON 1980; LIVELY 1987; HOWARD and LIVELY 1994, 1998) and in the evolution of male secondary sexual traits (HAMILTON and ZUK 1982; READ 1988; READ and HARVEY 1989; CLAYTON 1991; SAINO et al. 2003). Despite the fact that parasites are ubiquitous in nature and are deleterious to host fitness, there are considerable variations in susceptibility to parasite infection among host species (FREEHLING and MOORE 1993), among genetic strains within a species (YAN and NORMAN 1995), and among individuals within a population (DOBSON and HUDSON 1992). Our understanding of the evolution of resistance to parasitism is limited (RIGBY et al. 2002).

One purported genetic constraint for the evolution of resistance is fitness cost associated with resistance. Numerous conceptual (COLEY et al. 1985; HERMS and MATTSON 1992; FELTON and KORTH 2000) and mathematical models on the evolution of resistance (SIMMS and RAUSHER 1987; RENAUD and DE MEEUS 1991; FINEBLUM and RAUSHER 1995; RENAUD et al. 1996; BOOTS and HARAGUCHI 1999; SASAKI and GODFRAY 1999; KOELLA and BOETE 2003) assume that resistance to parasite infection is associated with fitness costs. There is indirect empirical evidence for cost of resistance to parasites in invertebrate as well as vertebrate hosts (BOOTS and BEGON 1993; FERDIG et al. 1993; KRAAIJEVELD and GODFRAY 1997; YAN et al. 1997; LANGAND et al. 1998; SASAKI and GODFRAY 1999; MORET and SCHMID-HEMPEL 2000; OPPERT et al. 2000; SASAKI 2000; SAYYED and WRIGHT 2001; KRAAIJEVELD et al. 2002). For example, Drosophila melanogaster larvae exhibited reduced competitive ability when adults were being selected for increased resistance to the parasitoid Leptopilina heterotoma (KRAAIJEVELD and GODFRAY 1997). Biomphalaria glabrata snails resistant to the blood fluke Schistosoma mansoni displayed lower fertility and survivorship than susceptible snails (WEBSTER and WOOLHOUSE 1999). In another snail species, B. brata individuals resistant to the fluke Echinostoma caproni reached maturity later than susceptible individuals (LANGAND et al. 1998). Evidence for cost of resistance is also seen in bacteria resistant to antibiotics (BOUMA and LENSKI 1988; FELDGARDEN and RILEY 1999; GUSTAFSSON et al. 2003) and in plants resistant to herbivores and herbicides (SIMMS and RAUSHER 1987; REBOUD and TILL-BOTTRAUD 1991; WILLIAMS et al. 1995; BERGELSON and PURRINGTON 1996; TIAN et al. 2003). Despite numerous reports on the costs of resistance to parasites, pathogens, herbivores, and antibiotics, there are also incidences where no fitness costs are detected in resistant populations (BERGELSON and PURRINGTON 1996; LITTLE et al. 2002; TIAN et al. 2003). For example, LITTLE et al. (2002) compared life-history characteristics of eight populations of the crustacean Daphnia magna that were resistant and susceptible to a bacterial pathogen and found that life-history characteristics of the resistant Daphnia did not differ from susceptible hosts.

Most published studies on the costs of resistance so far have used the approach of selection of resistant and susceptible populations and comparison of fitness between the two populations either in the absence or in the presence of parasites. Such approaches cannot differentiate pleiotropic effects of resistance genes from the effects of population life history and genetic correlation resulting from linkage disequilibrium. The goal of the present study is to examine whether the genes conferring resistance to parasite infection are associated with fitness costs through colocalization of the genes affecting fitness and resistance. We used the red flour beetle (Tribolium castaneum) and the rat tapeworm (Hymenolepis diminuta) system. This system is ideal for examining the genetic constraints of resistance evolution. Tribolium beetles in nature are intermediate hosts of the tapeworm and can be infected only when beetles ingest the tapeworm eggs. Parasites are not horizontally or vertically transmissible from beetle to beetle. The parasites are modestly virulent to the beetle hosts; infection reduces the beetle's relative fitness by 30% (YAN and STEVENS 1995), and the effect is dependent on infection intensity (YAN 1997). In addition, a preliminary fitness comparison between selected resistant and susceptible populations found that the resistant population exhibited lower fecundity and egg-to-adult viability than the susceptible population.

Mapping populations:

Two strains (TIW1 and cSM) of the red flour beetle T. castaneum were used to set up segregating populations for QTL mapping. The cSM strain was kindly provided by Michael Wade of Indiana University and TIW1 by Richard Beeman of Grain Marketing and Production Research Center in U.S. Department of Agriculture. The strain cSM has been used extensively in various ecological and genetic studies (e.g., WADE 1977; STEVENS 1989; YAN and STEVENS 1995; YAN 1997), and TIW1 was used for construction of an RAPD-based linkage map (BEEMAN and BROWN 1999). The two strains have been reared in the laboratory for >10 years and have never been exposed to the parasite during the laboratory culture process. For each strain, the population size in culture was normally >1000 beetles at every generation. The TIW1 strain exhibited significantly lower susceptibility to tapeworm infection than the cSM strain, but both strains exhibited within-strain variations in susceptibility to the parasites. Therefore, we prescreened the two beetle strains for highly susceptible cSM individuals and highly resistant TIW1 individuals for pairwise mating to establish appropriate QTL mapping populations. Offspring from three cSM pairs with the highest infection intensity (number of parasites in an infected individual) and from three TIW1 pairs with no parasite infection were reared to adults, while the offspring from other pairs were discarded. We repeated this process for three generations and selected resistant TIW1 and susceptible cSM individuals for pairwise mating (ZHONG et al. 2003). Beetles were raised in 8-dram shell vials containing 5 g standard medium (95% by weight fine-sifted whole-wheat flour and 5% dried, powdered brewer's yeast). Experimental vials were maintained in a dark incubator regulated at 29° and 70% relative humidity. All beetles described below for genetic mapping studies of resistance and fitness were reared under the same conditions.

To evaluate the generality of the QTL mapping results, we used two independent segregating populations. The first segregating population was generated from pairwise mating between a resistant TIW1 male and a susceptible cSM female (hereafter referred to as cross 1). The second was from pairwise mating between a susceptible cSM male and a resistant TIW1 female (hereafter referred to as cross 2). To increase recombination among the markers, we used F₃ individuals for QTL analyses. The mapping populations used in the current study were independent crosses, not the offspring of the F₂ populations used by ZHONG et al. (2003).

Measurement of fitness traits:

Two fitness traits (fecundity and egg-to-adult viability) were examined prior to exposure to tapeworm. Individual virgin F₃ females, 2 days postemergence, were paired with virgin males for 3 hr in a plastic petri dish with a thin layer of flour medium. Females were allowed to lay eggs for 1 week, and the eggs (fecundity) were counted. The adult offspring produced by each female were counted 5 weeks later. A total of 699 F₃ female beetles were examined for fitness traits (cross 1, n = 414; cross 2, n = 285). Egg-to-adult viability was calculated as the proportion of eggs that survived to adulthood.

Tapeworm infection:

The parental TIW1 and cSM populations, F₁ and F₃ individuals from cross 1 and cross 2, were evaluated for tapeworm susceptibility using the infection and dissection methods previously described (PAI and YAN 2003). All individuals were exposed to a comparable amount of tapeworm-infected feces (ZHONG et al. 2003). Two weeks following exposure to parasite eggs, 214 F₃ female beetles from cross 1 and 200 from cross 2 were dissected to determine infection intensity (the number of tapeworm parasites in a beetle). Beetle carcasses were collected and used for subsequent DNA analysis, but parasite tissues were discarded (ZHONG et al. 2003).

Molecular genotyping:

Genomic DNA was extracted individually from all the parents and from the F₁ and F₃ populations, following the phenol/chloroform method (SEVERSON 1997). All individuals were subjected to genotyping with amplified fragment length polymorphism (AFLP) markers. We used the previously developed AFLP linkage map based on the TIW1 x cSM cross (ZHONG et al. 2004). The map consists of 269 AFLP and 18 RAPD markers with an average marker resolution of 2 cM. We used 28 pairs of AFLP primers that yielded 169 informative markers for QTL analysis. The AFLP primer sequences and primer combinations were published previously (ZHONG et al. 2004). Among the 169 informative AFLP markers, 106 fragments were common to the two crosses. On the basis of that, the total recombination distance of AFLP markers in F₂ segregating populations was 573 cM (ZHONG et al. 2004), and the markers used in this study provided an average spacing of 3.4 cM between markers over the 10 linkage groups (LGs).

Data analysis:

Mapmanager QTX software (MANLY et al. 2001) was used to determine the QTL positions, the expected additive and dominance effects, and the phenotypic variance explained by individual QTL. The LOD threshold value for declaring the presence of a QTL was determined by permutation test (n = 1000) (CHURCHILL and DOERGE 1994). Ninety-five percent confidence intervals for the location of QTL were obtained by bootstrap analysis (VISSCHER et al. 1996). Three phenotypic traits (infection intensity, fecundity, and egg-to-adult viability) were subjected to QTL analysis. Females that did not produce any eggs were excluded from the analyses [60 female beetles for cross 1 (14.5%) and 28 for cross 2 (9.8%)]. A square-root transformation of the two fitness traits was used to normalize the phenotypic data; infection intensity data were not transformed because the frequency distribution did not deviate significantly from normality. Average levels of dominance were estimated using the ratio of dominance/additive effects (i.e., h = d/a). The type of gene action for each QTL was determined on the basis of h: underdominance or recessive if h < 0, additive if h = 0–0.20, partial dominance if h = 0.21–0.80, dominance if h = 0.81–1.20, and overdominance if h > 1.20 (STUBER et al. 1987). Individual QTL designations for parasite susceptibility have the following format: hds[n, y], where hds = H. diminuta susceptibility, n = the linkage group number, and y = the AFLP marker closest to the QTL. QTL for fecundity is designated as Fec[n, y], and egg-to-adult viability as Eav[n, y].

Phenotypic variability in infection intensity and fitness traits:

In cross 1 (cSM female x TIW1 male), the cSM female had 15 parasites and the TIW1 male 0 parasites. In cross 2 (cSM male x TIW1 female), the cSM male had 5 parasites and the TIW1 female 0 parasites. The average infection intensity of F₁ populations was 6.2 ± 0.9 (n = 20) for cross 1 and 3.5 ± 0.8 (n = 20) for cross 2. The mean infection intensity in F₃ populations was 4.8 ± 0.6 (range 0–19; n = 214) for cross 1 and 3.6 ± 0.5 (range 0–17; n = 200) for cross 2. In the F₃ population, the mean fecundity and the egg-to-adult viability was 14.4 ± 2.9 (range 1–68; n = 162) and 45.4 ± 5.3% (range 0–100%; n = 162) in cross 1 and 11.8 ± 2.5 (range 1–76; n = 145) and 33.7 ± 5.7% (range 0–100%; n = 145) in cross 2.

Significant positive correlation was found between beetle infection intensity and fecundity in the F₃ populations in both crosses (r = 0.332, P < 0.01, n = 214 for cross 1; r = 0.248, P < 0.05, n = 200 for cross 2). Infection intensity and egg-to-adult viability were not correlated (r = 0.164, P = 0.121, n = 214 for cross 1; r = 0.144, P = 0.155, n = 200 for cross 2). Fecundity was positively correlated with egg-to-adult viability in both crosses (r = 0.311, P < 0.01, n = 214 for cross 1; r = 0.570, P < 0.01, n = 200 for cross 2).

QTL for resistance to tapeworm infection:

We detected the same three QTL on LG3, LG6, and LG8 for beetle resistance to tapeworm infection in both segregating populations. The LOD score plots provide a basis for identifying molecular markers most closely linked to the QTL (Figure 1). These three QTL are designated as Hds[3,L1B1.69], Hds[6,L4A16.110], and Hds[8,L6B2.100]. Each QTL accounted for 15%, 32%, and 11% of the phenotypic variation in infection intensity in cross 1 and for 8%, 21%, and 15% in cross 2 (Table 1). Thus, these QTL collectively explained 58% and 44% of the total phenotypic variation in cross 1 and cross 2, respectively. Permutation tests indicated that all three QTL were statistically significant at the P < 0.01 level in both populations (Figure 1). The three QTL had additive effects ranging from 0.89 to 2.62 parasites and dominance effects ranging from 2.10 to 5.41 parasites (Table 1). QTL hds[3, L1B1.69] and hds[8, L6B2.100] exhibited large and positive h values, suggesting that the gene action at these two QTL was overdominance. In contrast, the gene action at QTL hds[6, L1A16.141] was underdominance or recessive.

View larger version (37K): In this window In a new window Download PPT slide   FIGURE 1.— Composite interval mapping of beetle resistance to tapeworm infection and fitness traits in the red flour beetle, T. castaneum. Cross 1 represents an F3 segregating population derived from a cross between a TIW1 male and a cSM female, while cross 2 is from a cross between a cSM male and a TIW1 female. Significance thresholds are indicated by dashed horizontal lines at LOD = 2.5 (genome-wide P < 0.05) and LOD = 9.6 (genome-wide P < 0.001), as determined by permutation tests (n = 1000) (CHURCHILL and DOERGE 1994). The recombination distance between markers is derived from the previously published AFLP linkage map based on F2 segregating populations (ZHONG et al. 2004).

 

View this table: In this window In a new window   TABLE 1 Genetic parameters estimated by composite interval mapping of the QTL affecting T. castaneum resistance to tapeworm infection and beetle fitness traits

 

QTL for fecundity:

In cross 1, three QTL affecting fecundity were detected on LG4, LG8, and LG9 at the P < 0.01 level (Figure 1). These were designated as Fec[4, L4A2.290], Fec[8, L6B2.100], and Fec[9, L1A16.208]. Each QTL explained 7%, 19%, and 10% of the phenotypic variation in fecundity (Table 1), and thus they collectively explained 36% of the total phenotypic variation. The QTL Fec[8, L6B2.100] had the largest additive gene effect on fecundity. The three QTL showed large positive h values, suggesting that the gene action at these three QTL was overdominance.

For cross 2, a total of four QTL affecting fecundity were detected on LGs 2, 3, 4, and 8 at P < 0.01 (Figure 1). The four QTL collectively explained 57% of the total phenotypic variation (Table 1). Two QTL identified in cross 1 (Fec[4, L4A2.290] and Fec[8, L6B2.100]) were identified in cross 2. Similar to cross 1, Fec[8, L6B2.100] showed the largest effect on fecundity, accounting for 20% of the variance in fecundity. Similar to cross 1, the gene action was dominance or overdominance at all four QTL (Table 1).

QTL for egg-to-adult viability:

In cross 1, four QTL on LG4, LG6, LG8, and LG10, respectively, were detected affecting egg-to-adult viability at the level of P < 0.01 (Figure 1). They were designated as Eav[4, L4A2.290], Eav[6, L1A16.116], Eav[8, L6B2.100], and Eav[10, L3A18.82]. These QTL collectively explained 59% of the total phenotypic variation. Similar to the QTL conferring beetle resistance, gene actions were mostly overdominance.

For cross 2, three QTL affecting egg-to-adult viability were detected on LG3, LG6, and LG8, respectively, at the P < 0.01 level (Figure 1). In addition to the two QTL detected in cross 1 (Eav[6, L1A16.116] and Eav[8, L6B2.100]), one new QTL (Eav[3, L1B1.69]) was identified in cross 2. These three QTL collectively explained 36% of the total phenotypic variation (Table 1).

Colocalization of QTL affecting beetle resistance and fitness traits:

The three QTL conferring beetle resistance to tapeworm parasites are located in the same genome regions where major fitness QTL reside (Figure 2). The two QTL for beetle resistance to parasite infection on LG3 and LG8 were colocalized with the QTL for fecundity and egg-to-adult viability. These QTL showed negative additive effect and negative dominance effect on the respective phenotypes, which means that the resistant strain TIW1 contributed alleles that increased the number of parasites, infection intensity, and fecundity. This is not surprising because the two traits showed strong positive correlation. Thus, the susceptible populations exhibited higher fecundity than the resistant population at this locus. On the contrary, the resistant population exhibited lower fecundity than the susceptible population at this locus. In other words, the resistance to parasites is costly. The third QTL for resistance to parasite infection on LG6 was located in the same genome region as the QTL affecting egg-to-adult viability. This QTL showed positive additive effect and negative dominance effect on the respective phenotypes, which means that the resistant strain TIW1 contributed alleles that decreased the number of parasites, increased resistance, and increased the egg-to-adult viability. It is important to note that QTL for fecundity and egg-to-adult viability were also found in linkage groups where QTL for resistance was not found (i.e., LG2, LG4, LG9, and LG10; Figure 2).

View larger version (38K): In this window In a new window Download PPT slide   FIGURE 2.— Colocalization of the QTL for resistance to tapeworm infection and fitness traits in T. castaneum. The recombination distance between markers is based on the AFLP linkage map constructed from F2 segregating populations (ZHONG et al. 2004). The length of the bar on the left of each chromosome represents the location of QTL at 95% confidence interval (VAN OOIJEN 1992; VISSCHER et al. 1996).

 

In this study, we simultaneously determined the genetic basis of beetle resistance to tapeworm infection and fitness traits using the QTL mapping technique. We identified a total of three QTL for resistance and five QTL for fecundity and egg-to-adult viability. The present study used F₃ segregating populations and detected three QTL conferring beetle resistance on the same chromosomal locations as those identified by the previous study involving independent F₂ segregating populations (ZHONG et al. 2003). Overall, the effects of these QTL on infection intensity and fitness traits were small to medium, indicating the polygenic nature of beetle resistance to parasite infection and fitness traits. Through colocalization of QTL affecting beetle resistance to tapeworm infection and fitness traits, we demonstrated that the QTL conferring resistance to parasite infection were in the same chromosomal regions where QTL affecting beetle fitness reside. In particular, two resistance QTL, Hds[3,L1B1.69] and Hds[8,L6B2.100], colocalize with the QTL affecting fecundity and egg-to-adult viability. One resistance QTL, Hds[6,L4A16.110], colocalizes with the QTL affecting egg-to-adult viability. In addition, other QTL for fecundity and egg-to-adult viability were found in linkage groups where QTL for resistance was not found.

Therefore, two interesting conclusions arise from these results. First, the genome regions where QTL conferring beetle resistance to tapeworms reside also contain the genes for beetle fitness. The genome regions where the QTL for parasite resistance are located explained the majority of the variance in fecundity (19 of 36% in cross 1 and 29 of 57% in cross 2) and in egg-to-adult viability in the two mapping populations (33 of 49% in cross 1 and 31 of 36% in cross 2). Therefore, this experiment provided strong evidence that parasite resistance is associated with host fitness. Second, other QTL affecting fecundity and egg-to-adult viability were also identified, but they were not in the same genome regions as the QTL for parasite resistance. Thus, the reduced fitness in the resistant population cannot be entirely attributed to parasite resistance genes or to other deleterious genes closely linked to the resistance genes.

In this study, we found that the detection of some QTL for fecundity and egg-to-adult viability varies between the two independent segregating populations. This phenomenon is consistent with findings in the literature that detection of quantitative trait loci may be sensitive to environmental effects and to the genetic background of the parental genotypes (PATERSON et al. 1991; LEIPS and MACKAY 2000). For example, PATERSON et al. (1991) demonstrated that some QTL affecting fruit size and soluble solids concentration in tomatoes were detected in one location but not in others, but the major QTL were always identified regardless of the environmental conditions. LEIPS and MACKAY (2000) reported that identification of six QTL affecting life span and the effects of QTL genotypes on life span vary between the genetic background of the parental individuals and larval rearing conditions. The lack of QTL detection congruency between mapping populations could be due to sampling errors if the sample size of the mapping populations is small, or there may be some sex-specific effects because we just used females in this study. Even with a large sample size, however, the statistical power of QTL detection is only moderate for QTL with smaller effects, as demonstrated by simulation studies (VAN OOIJEN 1992; BEAVIS et al. 1994; MELCHINGER et al. 1998). Because the sample size of our mapping populations is only moderate, it is possible that other QTL affecting beetle resistance and fitness with small effects may not be detected. For example, the current study and our previous study (ZHONG et al. 2003) used independent crosses and detected three resistance QTL on the same chromosomal regions, but the current study did not detect two QTL (hds[1, L2A16.155] and hds[10, L3A18.82]) that were identified in the previous study.

The fitness traits (fecundity and egg-to-adult viability) in the segregating populations of the present study were measured before the beetles were exposed to the tapeworm eggs. Thus, the significant positive correlation between infection intensity and fitness observed in the segregating populations was not due to parasite infection, but to some common genetic factors influencing these traits. Trait correlations may be attributable either to pleiotropic effects of single genes or to tight linkage of several genes that individually influence specific traits. Colocalization of the three genome regions on LG3, LG6, and LG8 that show significant phenotypic effects on both resistance to parasite infection and beetle fitness could result from the pleiotropic effects of the resistance genes on host fitness or from tight linkages between resistance genes and adverse deleterious mutations. Due to the limited resolution of QTL analysis, the colocalization of the QTL conferring resistance and fitness could not distinguish between these two possibilities. To ultimately prove or refute the pleiotropy hypothesis, fitness comparison between wild-type hosts and those in which the expression of the resistance genes has been knocked down or knocked out should be performed (FEDER and MITCHELL-OLDS 2003).

Information on the fitness costs associated with host resistance to parasite infection is crucial to our understanding of the appearance, spread, and distribution of resistance genes in natural populations (RIGBY et al. 2002). The issue of resistance evolution has important implications for agriculture, conservation, and vector-borne disease control. For example, since the use of genetic engineering to introduce parasite-resistance genes into natural mosquito populations to control malaria, dengue, or filarial worms has been proposed (JAMES 1992; COLLINS and BESANSKY 1994). Strategies to spread the parasite-resistance genes into natural vector populations should consider potential fitness costs caused by the resistance genes. Colocalization of genomic regions affecting both resistance and host fitness demonstrated in the present study suggests that the fitness constraint posed by the resistance genes should be taken into consideration when designing strategies for spreading parasite-inhibiting genes into natural insect populations.

We thank M. Karsay-Klein, T. Cottom, V. Penumetsa, and L. Bennett for technical assistance and an anonymous reviewer for critical comments. This research was supported by grant no. DEB 0076106 from the National Science Foundation to G.Y.

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Communicating editor: J. A. BIRCHLER

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