Abstract
Background Previous analysis suggested that the relative contribution of individual bones to regional skull lengths differ between inbred mouse strains. 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. Confirming negative pleiotropy and determining its basis may reveal important information about the maintenance of overall skull integration and developmental constraint on skull morphology.ResultsWe 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. 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. 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.ConclusionsA 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. This type of mechanism may have led to variation in the contribution of individual bones to the zygomatic arch noted across mammals. 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.
Highlights
Previous analysis suggested that the relative contribution of individual bones to regional skull lengths differ between inbred mouse strains
If there were differences in expression between genotypes, we looked for similarities between variation in RNA expression and the phenotypic effects of A-strain, C57, and WSB haplotypes on relative zygomatic bone length, which might indicate that variation in expression of these candidate genes is associated with the identified negative correlation in zygomatic bone lengths
The lengths of component bones of the zygomatic arch were negatively correlated within the Collaborative Cross (CC) Founder/F1 and Diversity Outbred (DO) samples, while cranial vault components were negatively correlated within the DO sample
Summary
Previous analysis suggested that the relative contribution of individual bones to regional skull lengths differ between inbred mouse strains. While a wide range of skull morphology has evolved across mammalian species, fundamental patterns of skull bone integration are generally conserved [1,2,3,4]. We investigate the genetic basis for negative correlations between adjacent skull bones in a large genetically heterogeneous population of mice. These negative correlations may serve as developmental constraints that support overall integration of the head while allowing for significant variation in the relative size of individual bones within subregions. 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
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