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Pleiotropic effects of individual gene loci on mandibular morphology.

Patterns of genetic correlation play an important role in evolutionary response to selection, potentially modifying both the rate and direction of evolution relative to a situation of independent inheritance (Lande 1979; Lande and Arnold 1983). It has been suggested that for adaptive evolution to proceed efficiently, traits that develop and function together must be inherited together, whereas functionally and developmentally unrelated traits must be inherited independently (Riedl 1978). This is the hypothesis of morphological integration (Olson and Miller 1958; Cheverud 1982, 1995, 1996a,b). This hypothesis has been supported by a wide range of studies in a variety of taxa (see Cheverud 1995).

To date, little is known concerning the genotypic basis of morphological integration. Morphological integration may occur because pleiotropic effects of single genes are generally restricted to functionally and developmentally related traits, leaving unrelated traits relatively uncorrelated. Alternatively, stabilizing selection may result in relatively high genetic correlations among functionally and developmentally related traits and relatively low correlations among unrelated traits through a balance of positive and negative pleiotropy (Lande 1980, 1984; Cheverud 1984). These alternatives differ in whether morphological integration is a feature of the genetic system itself, reflecting systems of pleiotropy, or whether the genetic system produces a random array of pleiotropic effects with genetic correlations representing a balance of positive and negative pleiotropy.

Riedl (1978) suggested that the genetic system itself should evolve so that the pattern of pleiotropic effects mimics the pattern of functional and developmental relationship. Recently, Wagner (1996; Wagner and Altenberg 1996) described the conditions under which pleiotropic effects would evolve so that characters participating in common functional and developmental systems are affected by a common set of genes, whereas functionally and developmentally unrelated traits are generally affected by separate sets of genes. From this viewpoint, the observed pattern of morphological integration is, in large part, a product of the evolution of pleiotropy rather than the evolution of genetic correlation through a changing balance of positive and negative pleiotropy.

To measure pleiotropy, one must measure the morphological effects of individual genes. Such effects have been largely inaccessible to quantitative geneticists. However, over the past few years advances in statistical and molecular genetics have combined to allow the measurement of the effects of quantitative trait loci (QTLs) on morphological characters (Lander and Botstein 1989; Haley and Knott 1992). By measuring the effects of QTLs on quantitative characters we will be able to determine the genotypic basis for correlations among traits and test hypotheses concerning patterns of pleiotropy as distinct from patterns of genetic correlation.

The hypothesis of morphologically integrated pleiotropy will be examined relative to single gene effects on mandibular morphology. The mandible is a complex skeletal organ displaying both developmental and functional heterogeneity (Atchley and Hall 1991; Atchley 1993; [ILLUSTRATION FOR FIGURE 1 OMITTED]). The two major portions of the rodent mandible are the corpus, or body, primarily composed of the molar and incisive alveolar regions supporting tooth roots, and the ascending ramus, composed of three muscular processes, the coronoid, the condyloid, and the angular, along with the central masseteric region. The major muscles of mastication insert into the ascending ramus. The condyloid process also carries the condyle for articulation with the cranium. Each region forms from a separate neural-crest-derived mesenchymal condensation. Condensation size affects the presence and future size of the region (Atchley and Hall 1991; Atchley 1993). The maintenance and further development of these mandibular regions also depends on the associated tissues. While skeletal muscular processes form prior to muscle development, their maintenance depends on continued muscle activity (Herring and Lakers 1981; Moore 1981; Atchley et al. 1984). Furthermore, if teeth are removed from the mandible, the surrounding alveolar bone is resorbed.

Studies of phenotypic and genetic morphological integration in the mandible have typically found that correlations are relatively high among traits measured on functionally and/or developmentally related parts of the mandible (Bailey 1956; Atchley et al. 1985a,b; Cheverud et al. 1991). In particular, correlations tend to be relatively high among alveolar traits and among measurements of the muscular processes. In his studies of mandibular morphology in congenic and recombinant inbred strains, Bailey (1985, 1986) found that individual chromosomal regions typically affected localized regions of the mandible, as expected if pleiotropy is limited to functionally and developmentally related traits. In this study we will measure the effects of individual QTLs on mandibular morphology to determine whether pleiotiopic effects are generally restricted to sets of functionally and developmentally related traits.


The study population is an [F.sub.2] generation produced by intercrossing two inbred mouse strains, Small (SM/J) and Large (LG/J). These two strains differ dramatically in overall size (Chai 1956), having been derived from separate selection experiments for small (MacArthur 1944) and large (Goodale 1938, 1941) body size, respectively. Loci carrying different alleles in the parental inbred strains will be heterozygous in the [F.sub.1] hybrid offspring. The [F.sub.2] generation is generated by intercrossing [F.sub.1] hybrid animals resulting in Mendelian segregation of alleles at varying loci.

Ten SM/J males were mated with 10 LG/J females producing 41 [F.sub.1] hybrid animals. The [F.sub.1] hybrids were intercrossed resulting in a total of 535 [F.sub.2] progeny. Individual [F.sub.1] dams produced several litters of varying size. Mated pairs were housed together until the dams were deemed pregnant, at which time the male was removed from the cage. Progeny were housed with their dam for three weeks and then were weaned and randomly allocated to single-sex cages of five animals each. The animals were maintained until 10 weeks of age, at which time they were sacrificed and necropsied. Organs were harvested and saved for DNA extraction. Carcasses were macerated with dermestid beetles and the right and left side mandibles separated in preparation for measurement. Complete mandibles were available for 480 animals. Further information on animal husbandry is reported in Cheverud et al. (1996).

The two-dimensional coordinates of 15 mandibular landmarks were obtained from lateral views of the right mandible using a digital video data collection system. A series of 21 linear distances were calculated from the landmark coordinate data [ILLUSTRATION FOR FIGURE 2 OMITTED]. These distances were chosen to delineate the size and shape of individual mandibular components and provide complete coverage of the mandible. For the most part, measurements sharing a landmark in common lie at right or obtuse angles to one another, minimizing positive correlations due to morphological redundancy (Cheverud and Richtsmeier 1986). The attribution of measurements to functional and developmental mandibular units is given in Table 1 and follows from discussions in Atchley and Hall (1991) and Atchley (1993), as summarized above. Traits were placed in specific mandibular units [ILLUSTRATION FOR FIGURE 1 OMITTED] when they crossed or formed a boundary of that unit.

Prior to genetic analysis, the effects of dam, litter size, experimental block, and sex were removed from the data, as described in Cheverud et al. (1996). These corrections resulted in a reduction of only 12% of the total variance in mandibular traits, but reducing the variance due to nongenetic factors enhances our ability to detect individual gene effects.

DNA was extracted from the spleens of individual mice using protocols described in Routman and Cheverud (1994, 1995). A total of 76 microsatellite markers were scored on the 535 [F.sub.2] hybrid mice. These represent a small subsample of the over 6000 variable microsatellite loci available for the inbred mouse strains (Dietrich et al. 1992, 1996). PCR amplification of microsatellite loci followed the protocol suggested by Dietrich et al. (1992) with minor modifications (Routman and Cheverud 1994, 1995). The marker loci cover all 19 autosomes. The X chromosome was not analyzed at this time because of insufficient molecular variability. The markers define a total of 55 intervals covering 1500 cM, for an average interval length of 27.5 cM. The specific loci scored and their map locations are given in Figure 3 and Cheverud et al. (1996). The map distances were obtained from MAPMAKER 3.0b (Lander et al. 1987; Lincoln et al. 1992a) as described in Routman and Cheverud (unpulb.).
TABLE 1. Mandibular measurements as shown in Figure 2. Measurements
are classified as belonging to the alveolar process (A) and its
subdivisions, the incisor (In) or molar (Mo) alveolus, or to the
ascending ramus (M) and its subdivisions, the coronoid process
(Cr), the condyloid process (Cn), the angular process (Ag), or the
masseteric region (Ms).

number          Trait name                        Region

1          Coronoid height                        M, Cr
2          Superior condylar length               M, Cn
3          Condylar width                         M, Cn
4          Inferior condylar length               M, Cn
5          Condylar base length                   M, Cn, Ms
6          Posterior angular height               M, Ag
7          Posterior angular length               M, Ag
8          Anterior angular length                M, Ag
9          Superior angular length                M, Ag, Ms
10         Posterior corpus height                A, In, M, Ms
11         Coronoid base length                   M, Cr, Ms
12         Posterior-inferior basal length        A, In
13         Anterior-inferior basal length         A, In
14         Inferior incisor alveolus length       A, In
15         Incisor alveolus width                 A, In
16         Superior incisor alveolus length       A, In
17         Anterior corpus height                 A, In
18         Molar alveolus height                  A, Mo
19         Superior molar alveolus length         A, Mo
20         Inferior molar alveolus length         A, Mo
21         Superior coronoid length               M, Cn

The additive and dominance genotypic effects of QTLs on mandibular traits were measured using the interval mapping methods of Lander and Botstein (1989) as realized in the MAPMAKER/QTL 1.1b program (Paterson et al. 1988; Lincoln et al. 1992b). Models were fit for each character separately at 2-cM intervals along the chromosomes. The chromosomal location with the highest LOD score (linkage odds score) is marked as the most likely location for a QTL affecting the trait. The model specified includes the additive genotypic value (a) and the dominance genotypic value (d). The percent of [F.sub.2] phenotypic variance accounted for by the QTL is also reported. Percentages of variance accounted for by a QTL do not have a monotonic relationship with the LOD score because of different map densities on different chromosomes. When significant results were obtained, the chromosomal pattern of genetic effects and significance were inspected to determine whether a second QTL may be present on the chromosome. Indications of a potential second QTL include a secondary peak LOD score, an exceptionally wide LOD score peak, or abrupt changes in the sign of the estimated additive or dominance effects. If a second QTL was suspected, a series of two QTL models were fit to the data and accepted if their likelihood exceeded that of a one locus model at the 5% level.

Traits that are affected by a limited chromosomal region were considered as being affected by a single QTL when there was a lack of significant heterogeneity in map position among the traits. The significance of map-position heterogeneity was tested by calculating twice the difference in log-likelihood between a model in which all significant traits map to a common chromosomal location and a model allowing each trait its own location and comparing this value with a [[Chi].sup.2]-distribution with p - 1 degrees of freedom, where p is the number of traits. This test ignores intertrait correlations and therefore may be conservative in grouping traits together. The common position for a set of traits was set at their average QTL map position, each trait's position being weighted by its log-likelihood in determining the average. Given this approach, it is possible that closely linked QTL could be responsible for affects attributed here to a single locus. Our analysis is limited by the resolution provided by recombination in the gametes that produced the 535 [F.sub.2] animals raised for this study. Finer resolution may be obtained by fine-mapping genomic regions of interest in later generations (Darvasi and Soller 1995). However, overinclusive aggregation of QTL-effect locations into a single QTL when the effects are actually due to multiple linked QTLs will bias the results against the hypothesis of morphological integration, unless it is supposed that closely linked genes tend to affect closely related morphological traits.

Statistical significance of the QTL models were evaluated using LOD scores. Because of multiple comparisons problems (Lander and Botstein 1989; Lander and Schork 1994), the level of statistical significance for a given LOD score was determined by simulation. Five hundred simulated populations were produced by randomly generating 535 trait values from a normal distribution with a mean of zero and a variance of one. These random phenotypic data were combined with the observed genotypic data and each chromosome analyzed by interval mapping to obtain a distribution of LOD scores under the null hypothesis of no QTL effect (Cheverud et al. 1996). The 90th, 95th, and 99th percentile of the LOD score distributions estimated the 10%, 5%, and 1% critical values for LOD scores. Results significant at the 10% level are presented because they often correspond to locations with significant results for other mandibular characters.

It is expected that some false positive results will be obtained given the large number of significance tests performed for this study. With 19 chromosomes and 21 traits, one expects about one false positive result per trait at the 5% level, or 21 false attributions of traits to chromosomal locations (QTLs) scattered randomly across the genome. The hypotheses tests performed for this study do not depend on the positive nature of any single chromosomal location-trait association observed. Instead, the tests depend on the pattern of traits associated with each QTL. We do not expect false positive results to produce clusters of developmentally and functionally related traits in restricted chromosomal regions. Thus, to the extent that false positive results are produced in this analysis, they will bias our findings against morphological integration.

Hypotheses of morphological integration were tested using two-way tables and Fisher's exact test (Sokal and Rohlf 1995) associating sets of functionally and developmentally related traits with sets of traits significantly affected by a QTL. Magnitude of association between trait group and significant QTL effect was measured by the Phi coefficient (Sokal and Rohlf 1995). For each QTL, traits were cross-classified as being significantly affected (1) or not (0) and as representing either the alveolar (1) or ascending ramus (0) region of the mandible, as specified in Table 1. A positive Phi coefficient indicates an alveolar QTL because more alveolar traits are associated with such a QTL than expected given random assignment of traits to QTLs. A negative Phi coefficient indicates an ascending ramus QTL. QTLs may not produce significant results on this test because only subsets of the alveolar or ascending ramus regions may be affected. Therefore, the traits significantly affected by each QTL were also tested for significant association with each local region, the molar and incisor alveolar regions and the coronoid, condyloid, angular, and masseteric regions of the ascending ramus [ILLUSTRATION FOR FIGURE 1 OMITTED] using the Phi coefficient and a one-way Fisher's exact test. (A one-way test is used here because only positive association is of interest.)


The additive (a) and dominance (d) genotypic values for QTLs affecting individual mandibular measurements are given in Table 2. Each chromosome carries significant QTLs for aspects of mandibular morphology. Considering only those restricted chromosomal regions affecting multiple traits, 37 QTLs are identified affecting mandibular morphology. Twenty-six of these QTLs have significant effects on more than two traits. The QTLs discovered are small to moderate in their effects, no effect exceeding 20% of the [F.sub.2] phenotypic variance and only a few exceeding 10%.

As expected, most additive effects are positive, indicating that alleles derived from the LG/J strain tend to increase size. QTMAN18-1 and QTMAN19-1 are exceptions to this trend with the SM/J allele often leading to larger size. The LG/J allele is typically dominant, or partially dominant, to the SM/J allele for these traits, although many exceptions occur, such as for traits affected by QTMAN6-2, QTMAN8-1, QTMAN1O-1, and QTMAN16-1.

Some loci display contrasting positive and negative genotypic values for different traits indicating local shape variation. For example, at QTMAN8-1 both coronoid height (1) and superior condyloid length (2) have negative additive and dominance values, in contrast to most other measurements. This indicates a relatively shallow mandibular notch for the LG/J homozygotes and heterozygotes. QTMAN17-2 affects inferior mandibular lengths with a positive additive value for [TABULAR DATA FOR TABLE 2 OMITTED] anterior angular length (8) and negative values for posterior angular length (7) and anterior inferior basal length (13). This represents a relatively deeply notched inferior mandibular corpus for LG/J homozygotes at this locus. Also, QTMAN33 has a positive additive value and overdominance for inferior incisor alveolar length (14) and a negative additive value and underdominance for incisor alveolar width (15). This indicates that genotypes with a long incisor sleeve (LG/J homozygotes and heterozygotes) extend ossification further along the narrowing, projecting incisor.

The genomic position and morphological pattern produced by each QTL is displayed in Figure 4. Tests for morphological integration of pleiotropic effects are presented in Table 3. Of the 26 QTLs affecting more than two traits, seven (27%) are significantly associated with the general contrast of alveolar versus ascending ramus traits. QTMAN1-1, QTMAN4-1, QTMAN10-2, QTMAN13-1, and QTMAN15-2 affect ascending ramus traits while QTMAN6-1 and QTMAN10-1 affect alveolar traits. The association between major mandibular regions and regions affected by individual QTLs is very highly significant when summed across all QTLs ([[Chi].sup.2] = 107.128, 37 df, P [less than] 0.001) or when considered only for QTLs with more than two significant effects ([[Chi].sup.2] = 89.482, 26 df, P [less than] 0.001).

Most of the QTLs are significantly associated with more localized mandibular regions. Five QTLs are significantly associated with the coronoid process (QTMAN3-2, QTMAN4-2, QTMAN13-1, QTMAN15-3, and QTMAN19-1), four with the condyloid process (QTMAN1-1, QTMAN9-1, QTMAN10-2, and QTMAN15-2), one with the angular process (QTMAN17-2), and three with the masseteric region (QTMAN1-1, QTMAN4-2, and QTMAN19-1). The three QTLs associated with the masseteric region are also associated with the condyloid or coronoid process. Furthermore, three QTLs (QTMAN2-2, QTMAN41, and QTMAN8-1) nearly exclusively affect the ascending ramus, although tests of association failed to reach significance. Five QTLs are significantly associated with the incisor alveolus (QTMAN1-2, QTMAN3-1, QTMAN3-3, QTMAN12-2, and QTMAN13-2) and six with the molar alveolus (QTMAN6-1, QTMAN6-2, QTMAN10-1, QTMAN11-4, QTMAN15-1, and QTMAN17-1). Only six of the 26 QTLs affecting more than two traits affect traits from across the whole mandible (QTMAN112, QTMAN11-3, QTMAN12-1, QTMAN14-1, QTMAN14-2, and QTMAN16-1).

Of the QTLs affecting more than two traits, 50% affect the ascending ramus or its components, 27% affect the alveolus or its components, and 23% affect the whole mandible. These results indicate that pleiotropic effects of individual genes are restricted generally to sets of functionally and developmentally related traits. The negative pleiotropy detected here was within local mandibular regions.


We discovered many quantitative trait loci with small to moderate effects on mandibular morphology. This corresponds to the usual quantitative genetic assumption that variation in quantitative traits is due to many loci of small sub-equal effects (Falconer and Mackay 1996). These QTLs were spread across the mouse genome. Typically, the LG/J allele resulted in a longer measurement. When dominance was present, the LG/J allele was typically dominant to the SM/J allele, although important exceptions to this trend occur.

Most chromosomal regions affecting mandibular morphology have region-specific effects, being restricted largely to portions of the muscular processes of the ascending ramus (50%) or to the alveolar processes of the mandibular corpus (27%). A minority of loci (23%) seemed to affect all parts of the mandible. For this contrast of the SM/J and LG/J strains, mandibular morphological integration is due to pleiotropy being restricted to sets of functionally and developmentally related traits. These results reproduce Bailey's (1985, 1986) findings for mandibular morphology in congenic and recombinant inbred strains. Morphological integration in the mandible appears to be a feature of the genetic system rather than being due to a balance between positive and negative pleiotropy.

Little is known about the evolution of the genetic system or specifically about the evolution of pleiotropy. In an interesting model of morphological disintegration, Wagner (1996; Wagner and Altenberg 1996) proposes that universal pleiotropy is the primitive state for trait sets and that restricted pleiotropy, such as we report here, arises through selection for modularization. Whether universal pleiotropy is indeed the primitive state for multicellular organisms, as suggested by Wagner, is speculation but is accepted here for the sake of argument. In Wagner's model, a largely separate genetic "module" evolves for each set of functionally and developmentally related traits. With selection for modularization, pleiotropy for functionally related, coselected characters is reinforced, whereas pleiotropy for unrelated traits is suppressed. Suppression is accomplished by differential epistasis in which a "modifier" locus suppresses variation caused by the target locus in traits unrelated to the coselected set. Differential epistasis results in modularization, in which the effects of specific genes are restricted to a functionally related set of traits. It is hypothesized that modularization is required for adaptive evolution (Riedl 1978; Wagner 1996). The results obtained here for mandibular morphology are consistent with the modularization model in that most QTLs have specific effects on functionally and developmentally integrated mandibular regions. It remains to be seen whether the population produced by this intercross also displays variability in differential epistasis for these traits.

Loci affecting mandibular characters can do so in a variety of ways: (1) by directly affecting the size and growth rate of cell condensations and the rate and extent of bony extracellular matrix deposition; (2) indirectly through the epigenetic effects of soft tissues interacting with the bony mandible; or (3) indirectly through systemic effects induced by hormonal systems regulating overall body growth (Atchley and Hall 1991). It is possible that many of the effects on muscular processes are due to genes that affect muscle size, thereby affecting the force exerted at muscle attachments and consequently the size of the corresponding muscular processes. These genes could either be systemic in their effects or specifically expressed in muscle tissue. The effects of some loci even seem restricted to single muscular processes, such as the coronoid, condyloid, or angular process. Likewise, loci with effects on the alveolus may be expressed in tooth development, since the size of the alveolar region is controlled, in large part, by tooth development.

The possibility that some of the QTLs for mandibular morphology have systemic effects is supported by our earlier analysis of genes affecting 10-week body weight (Cheverud et al. 1996). The 17 loci affecting adult weight share 12 map locations with the 37 loci affecting mandibular morphology (QTMAN1-1, QTMAN2-2, QTMAN3-2, QTMAN4-1, QTMAN6-2, QTMAN9-1, QTMAN10-2, QTMAN11-4, QTMAN12-1, QTMAN13-1, QTMAN14-2, and QTMAN15-2). These shared chromosomal regions are candidates for genes acting on the mandible through systemic mechanisms, although it is still possible that separate, linked loci are involved in control of weight and mandibular morphology. Only five of these 12 shared loci also affect total mandibular length (unpubl. results), indicating that the systemic effects of the other six loci may act on the mandible through intermediate tissues, such as muscle or teeth. Further work on separate components of body weight, such as skeletal size and fatness may help clarify the means by which particular loci affecting body weight also affect mandibular features. We may expect genes affecting fatness, but not skeletal size, not to affect the mandible.

The genetic architecture underlying quantitative traits has been largely the realm of assumption and theoretical debate. The advent of quantitative trait locus studies allows for the delineation of the effects of individual genes on complex phenotypes and an unraveling of the genetic system underlying these traits (Liu et al. 1996; Lyman et al. 1996). In particular these studies offer the potential for investigating the evolution of genetic architecture itself. In the present study, patterns of pleiotropy among mandibular characters were found to correspond to expectations based on functional and developmental relationships. The pleiotropic effects of genes are commonly restricted to functionally and developmentally integrated modules.


We thank G. Conroy for the use of digitizing equipment and C. Perel, K. Cothran, B. van Swinderen, E. Cheverud, and F. M. Duarte for help scoring molecular markers. We are especially grateful for the insightful comments made by L. Leamy and G. Wagner on earlier drafts of this paper. This work was supported by National Science Foundation grant DEB-9419992.


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Author:Cheverud, James M.; Routman, Eric J.; Irschick, Duncan J.
Date:Dec 1, 1997
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