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22q11.2DS research ventures down the evolutionary tree

Guna et al. Journal of Neurodevelopmental Disorders (2015) 7:18.

The recent manuscript by Alina Guna, Nancy Butcher and Anne Bassett has initiated a long-overdue discussion on the use of invertebrate model systems for the study of 22q11.2DS. Unfortunately, the utility of less complex organisms in the study of very complex human diseases is lost on many medical professionals and human geneticists. After all, what could a nematode that has no brain tell us about processes in the elaborate human brain? Is the study of this disease in such organisms feasible and advisable? Guna et al. offers a thorough examination of these questions.

The manuscript begins with an updated survey of the genes in the disease-critical region. Recent months have seen a paradigm shift in our understanding of the genome. We now realize that, rather than being lousy with un-used, unimportant sequences between the scientifically-interesting coding genes, our genome is instead replete with noncoding genes, small peptides, and epigenetic marks, the roles of which are just beginning to be understood. It is fitting, then, that Guna and colleagues have re-evaluated the disease region in light of this new understanding of the genome, providing the community with an updated view of 22q11.2 genes. The authors then applied this information to a search of the genomes of all common model organisms for orthologues of 22q11.2 deletion genes. This paper summarizes published phenotypic information on existing mutant and knockdown alleles in zebrafish, Drosophila, and C. elegans.

Finally, the authors undertake a thoughtful discussion of how these organisms might be useful for 22q11.2DS researchers. Guna et al emphasize that simple organisms may make for poor models of multifaceted neural constructs such as anxiety or learning. However, these models have numerous advantages for the study of molecular and genetic pathways in which 22q11.2 genes are involved. For example, short life cycles, simplified genomes and cells, and well-established tools allow for whole genome forward and reverse genetic screens as well as pharmacologic screens in such organisms. Also, the study of a conserved gene in a stripped down cell may allow for more direct identification of molecular function without the burden of false positive results commonly obtained from highly complex cells and tissues. The findings gathered and discussion offered in this manuscript provide a roadmap for the potential use of some powerful genetic tools that have been largely un-explored by the 22q11.2 research community.