Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease.

Human palatal clefting is debilitating and difficult to rectify surgically. Animal models enhance our understanding of palatogenesis and are essential in strategies designed to ameliorate palatal malformations in humans. Recent studies have shown that the zebrafish palate, or anterior neurocranium, is under similar genetic control to the amniote palatal skeleton. We extensively analyzed palatogenesis in zebrafish to determine the similarity of gene expression and function across vertebrates. By 36 hpf palatogenic cranial neural crest cells reside in homologous regions of the developing face compared to amniote species. Transcription factors and signaling molecules regulating mouse palatogenesis are expressed in similar domains during palatogenesis in zebrafish. Functional investigation of a subset of these genes, fgf10a, tgfb2, pax9 and smad5 revealed their necessity in zebrafish palatogenesis. Collectively, these results suggest that the gene regulatory networks regulating palatogenesis may be conserved across vertebrate species, demonstrating the utility of zebrafish as a model for palatogenesis.

Mutation of SATB2 causes cleft palate in humans. To understand the role of SATB2 function in palatogenesis, SATB2 analyses in vertebrate model systems will be essential. To facilitate these analyses, we have performed a cross-species comparison of SATB2 structure and function across three vertebrate model systems: mouse, chick, and zebrafish. We find that the SATB2 transcript is highly conserved across human, mouse, chick, and zebrafish, especially within the Satb2 functional domains. Furthermore, our expression analyses demonstrate that SATB2 is likely to have similar functions in vertebrate model organisms and humans during development of the facial processes and secondary palate. Together, these data suggest an evolutionary conserved role for SATB2 during development of the face and palate across vertebrates. Moreover, expression of zebrafish satb2 in the anterior neurocranium supports the utility of the anterior neurocranium as a simplified model of amniote palatogenesis. Developmental Dynamics 239:3481-3491,