Within the craniofacial skeleton, a pair of negatively correlated and adjacent bone lengths provides a relatively simple system within which to search for genes underlying negative pleiotropy. Negative correlations between raw linear distance measurements are rare and can be evidence of scale-independent negative pleiotropy, which exists when genetic variation leads to an opposite phenotypic effect on two traits. Random pairs of linear distances across the skull are expected to display positive correlations driven by the overall growth of the integrated head. Identifying genetic factors underlying this type of developmental constraint is important for understanding the basis of morphological integration and will illuminate critical connections between developmental and evolutionary processes. These negative correlations may serve as developmental constraints that support overall integration of the head while also allowing for significant variation in the relative size of individual bones within subregions. Here, we investigate the genetic basis for negative correlations between adjacent skull bones in a large genetically heterogeneous population of mice. Understanding the genetic basis for this integration and developmental constraint is critical for illuminating how genes and development can influence processes of evolution. The same factors that reinforce the development of an integrated head can serve as developmental constraints on the directions that evolution can take. This shared morphological pattern reflects conserved tissue origins, ossification patterns, and strong selective pressure for an adequately integrated and functional head. While a wide range of skull morphology has evolved across mammalian species, fundamental patterns of skull bone integration are generally conserved. The skull is a complex structure that supports and protects tissues critical for survival, including the brain, sense organs, and masticatory apparatus. Given that similar genetic and developmental mechanisms may underlie negative correlations in other parts of the skull, these results provide an important step toward understanding the developmental basis of evolutionary variation and constraint in skull morphology. This type of mechanism may have led to variation in the contribution of individual bones to the zygomatic arch noted across mammals. ConclusionsĪ genomic region underlying negative pleiotropy of two zygomatic arch bones was identified, which provides a mechanism for antagonism in component bone lengths while constraining overall zygomatic arch length. Candidate genes in this region were identified and real-time PCR of the maxillary processes of DO founder strain embryos indicated differences in the RNA expression levels for two of the candidate genes, Camkmt and Six2. Through gene association mapping of a large heterogeneous population of Diversity Outbred (DO) mice, we identified a quantitative trait locus on chromosome 17 driving the antagonistic contribution of these two zygomatic arch bones to total zygomatic arch length. We identified negative correlations between the lengths of the frontal and parietal bones in the midline cranial vault as well as the zygomatic bone and zygomatic process of the maxilla, which contribute to the zygomatic arch. Confirming negative pleiotropy and determining its basis may reveal important information about the maintenance of overall skull integration and developmental constraint on skull morphology. If the negative correlation of adjacent bone lengths is associated with genetic variation in a heterogeneous population, it would be an example of negative pleiotropy, which occurs when a genetic factor leads to opposite effects in two phenotypes. Previous analysis suggested that the relative contribution of individual bones to regional skull lengths differ between inbred mouse strains.
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