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Craniofacial asymmetry is a convergent trait widely distributed across animals that colonize the extreme cave environment. Although craniofacial asymmetry can be discerned easily, other complex phenotypes (such as sensory organ position and numerical variation) are challenging to score and compare. Certain bones of the craniofacial complex demonstrate substantial asymmetry, and co-localize to regions harboring dramatically expanded numbers of mechanosensory neuromasts. To determine if a relationship exists between this expansion and bone fragmentation in cavefish, we developed a quantitative measure of positional symmetry across the left-right axis. We found that three different cave-dwelling populations were significantly more asymmetric compared to surface-dwelling fish. Moreover, cave populations did not differ in the degree of neuromast asymmetry. This work establishes a method for quantifying symmetry of a complex phenotype, and demonstrates that facial bone fragmentation mirrors the asymmetric distribution of neuromasts in different cavefish populations. Further developmental studies will provide a clearer picture of the developmental and cellular changes that accompany this extreme phenotype, and help illuminate the genetic basis for facial asymmetry in vertebrates. [ABSTRACT FROM AUTHOR]

SUMMARY Animals that colonize dark and nutrient-poor subterranean environments evolve numerous extreme phenotypes. These include dramatic changes to the craniofacial complex, many of which are under genetic control. These phenotypes can demonstrate asymmetric genetic signals wherein a QTL is detected on one side of the face but not the other. The causative gene(s) underlying QTL are difficult to identify with limited genomic resources. We approached this task by searching for candidate genes mediating fragmentation of the third suborbital bone (SO3) directly inferior to the orbit of the eye. We integrated positional genomic information using emerging Astyanax resources, and linked these intervals to homologous (syntenic) regions of the Danio rerio genome. We identified a discrete, approximately 6 Mb, conserved region wherein the gene causing SO3 fragmentation likely resides. We interrogated this interval for genes demonstrating significant differential expression using mRNA-seq analysis of cave and surface morphs across life history. We then assessed genes with known roles in craniofacial evolution and development based on GO term annotation. Finally, we screened coding sequence alterations in this region, identifying two key genes: transforming growth factor β3 ( tgfb3) and bone morphogenetic protein 4 ( bmp4). Of these candidates, tgfb3 is most promising as it demonstrates significant differential expression across multiple stages of development, maps close (<1 Mb) to the fragmentation critical locus, and is implicated in a variety of other animal systems (including humans) in non-syndromic clefting and malformations of the cranial sutures. Both abnormalities are analogous to the failure-to-fuse phenotype that we observe in SO3 fragmentation. This integrative approach will enable discovery of the causative genetic lesions leading to complex craniofacial features analogous to human craniofacial disorders. This work underscores the value of cave-dwelling fish as a powerful evolutionary model of craniofacial disease, and demonstrates the power of integrative system-level studies for informing the genetic basis of craniofacial aberrations in nature. [ABSTRACT FROM AUTHOR]

Natural model systems evolving under extreme environmental pressures provide the opportunity to advance our knowledge of how the craniofacial complex evolves in nature. Unlike traditional models, natural systems are less inbred, and, therefore, better model the complex variation of the human population. Owing to the nature of certain craniofacial aberrations in blind Mexican cavefish, we suggest that this organism can provide new insights to a variety of craniofacial changes. Diverse cranial features have evolved in natural cave-dwelling Astyanax fish, which have thrived in the unforgiving darkness and nutrient-poor environment of the cave for countless generations. While the genetic and environmental underpinnings of various cranial anomalies have been investigated for decades, a comprehensive characterization of their molecular and developmental origins remains incomplete. Cavefish provide numerous advantages given the availability of genomic resources, developmental and molecular tools, and the presence of a normative surface-dwelling "ancestral" surrogate for comparative studies. By leveraging the frequency of abnormal and asymmetric cranial features in cavefish, we anticipate advances in our knowledge of the etiologies of irregular cranial features. Extreme adaptations in cavefish are expected to offer new insights into the complex and multifactorial nature of craniofacial disorders and facial asymmetry. Anat Rec, 2018. © 2018 American Association for Anatomy., (© 2018 American Association for Anatomy.)