Genetic mapping of molar size relations identifies inhibitory locus for third molars in mice

Abstract

Molar size in Mammals shows considerable disparity and exhibits variation similar to that predicted by the Inhibitory Cascade model. The importance of such developmental systems in favoring evolutionary trajectories is also underlined by the fact that this model can predict macroevolutionary patterns. Using backcross mice, we mapped QTL for molar sizes controlling for their sequential development. Genetic controls for upper and lower molars appear somewhat similar, and regions containing genes implied in dental defects drive this variation. We mapped three relationship QTLs (rQTL) modifying the control of the mesial molars on the focal third molar. These regions overlap Shh, Sostdc1, and Fst genes, which have pervasive roles in development and should be buffered against new variation. It has theoretically been shown that rQTL produces new variation channeled in the direction of adaptive changes. Our results provide evidence that evolutionary/disease patterns of tooth size variation could result from such a non-random generating process.

Fig. 1. QTL mapping for each individual molar and the two rows

Focal molar or row is colorized in green on the 3D dental model represented on the upper right corners. The four upper mapping panels are upper molars (row, M¹, M², M³), and the four lower panels are lower molars (row, M₁, M₂, M₃). Horizontal lines represent 5% genomewide thresholds from 100,000 permutations for each modeling. Gray lines are LOD profiles and 5% genomewide thresholds for the upper (~Sex + DoC + Q) and lower molar rows (∼DoC + Q). Black lines represent results for M¹~Sex + DoC + Q, and for M₁~Sex + DoC + Q. Green lines represent results of the FULL models for second (M²~M¹ + Q + M¹ × Q and M₂~Sex + M₁ + Q + M₁ × Q) and third molars (M³~M² + Q + M² × Q and M₃~DoC + M₁ + M₂ + Q + M₁ × Q + M₂ × Q); Maroon lines represent the ADD models (i.e., the four preceding models but without interaction) and light green lines represent the INTER mapping (i.e., only the interaction part of the FULL model). Yellow lines represent the results for the NoCOV models (i.e., the four models but without molar covariates). The NoCOV genomewide threshold is confounded with the ADD threshold at LOD = 3 and therefore not visible. In the NoCOV yellow mapping, both direct and indirect QTLs have an effect. In the ADD maroon mapping, only direct QTLs have an effect. In the FULL green mapping, both direct QTLs and rQTLs have an effect whereas the INTER light green mapping corresponds to the rQTL only (Color online)

Fig. 2. Additive effect trace plot along chromosome 7 for M₂ and M₃ centroid sizes and the centroid sizes of the two possible genotypes at the two QTLs

Envelopes and error bars are standard errors of the mean. For the left panel, centroid size is defined conditional on the covariate included in the additive model (M₂~Sex + M₁, M₃~DoC + M₁ + M₂). Genotype A relates A/J strain and B relates C57BL6/J strain