Cichlid fishes as a model to understand normal and clinical craniofacial variation

Abstract

We have made great strides towards understanding the etiology of craniofacial disorders, especially for ‘simple’ Mendelian traits. However, the facial skeleton is a complex trait, and the full spectrum of genetic, developmental, and environmental factors that contribute to its final geometry remain unresolved. Forward genetic screens are constrained with respect to complex traits due to the types of genes and alleles commonly identified, developmental pleiotropy, and limited information about the impact of environmental interactions. Here, we discuss how studies in an evolutionary model – African cichlid fishes – can complement traditional approaches to understand the genetic and developmental origins of complex shape. Cichlids exhibit an unparalleled range of natural craniofacial morphologies that model normal human variation, and in certain instance mimic human facial dysmorphologies. Moreover, the evolutionary history and genomic architecture of cichlids make them an ideal system to identify the genetic basis of these phenotypes via quantitative trait loci (QTL) mapping and population genomics. Given the molecular conservation of developmental genes and pathways, insights from cichlids are applicable to human facial variation and disease. We review recent work in this system, which has identified lbh as a novel regulator of neural crest cell migration, determined the Wnt and Hedgehog pathways mediate species-specific bone morphologies, and examined how plastic responses to diet modulate adult facial shapes. These studies have not only revealed new roles for existing pathways in craniofacial development, but have identified new genes and mechanisms involved in shaping the craniofacial skeleton. In all, we suggest that combining work in traditional laboratory and evolutionary models offers significant potential to provide a more complete and comprehensive picture of the myriad factors that are involved in the development of complex traits.

Genetic analyses in Lake Malawi cichlids identify new roles for Fgf signaling in scale shape variation

“…We have argued previously that a comparative approach in non-traditional models holds much promise for this pursuit 64 . Here we illustrate this idea using variation in scale morphology as a model.…”

The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species

“…As such, we would not expect large-fold differential gene expression and we are keenly aware that subtle changes in gene expression can have significant phenotypic consequences. For instance, small changes to the quantitative amount of Shh expression in the developing head of chickens has substantive phenotypic consequences for craniofacial morphology [9, 63]. Evolution operates by tinkering with existing genetic/developmental processes, and the striking morphological differences among species of pupfishes may be produced by slight modifications to gene expression.…”

“…Model organisms such as zebrafish or medaka lack the phenotypic diversity of interest, but non-model organisms like cichlid fishes or pupfishes display this diversity and are also easy to rear in the lab [9, 11–13]. From a developmental perspective, specification and differentiation of skeletal head elements depends on complex interactions between the brain, facial epithelium, neural crest derived mesenchyme, and head endoderm during embryonic development [14–17].…”

Animal models of craniofacial anomalies

“…Chicken embryos are also easily manipulated and have been used to model both genetic and environmental factors contributing to craniofacial anomalies (Kiecker, 2016;Schock et al, 2015). Several comparative systems are also highlighted, such as avian models, and the new and emerging cichlid fishes and catsharks (Fish, 2015;Powder and Albertson, 2015;Rasch et al, 2016). Finally, a very intriguing paper proposes the use of wasp genetics to understand complex genetic interactions in the craniofacial complex (Werren et al, 2015).…”