Systematic discovery of nonobvious human disease models through orthologous phenotypes

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Abstract
Biologists have long used model organisms to study human diseases, particularly when the model bears a close resemblance to the disease. We present a method that quantitatively and systematically identifies nonobvious equivalences between mutant phenotypes in different species, based on overlapping sets of orthologous genes from human, mouse, yeast, worm, and plant (212,542 gene-phenotype associations). These orthologous phenotypes, or phenologs, predict unique genes associated with diseases. Our method suggests a yeast model for angiogenesis defects, a worm model for breast cancer, mouse models of autism, and a plant model for the neural crest defects associated with Waardenburg syndrome, among others. Using these models, we show thatSOX13regulates angiogenesis, and thatSEC23IPis a likely Waardenburg gene. Phenologs reveal functionally coherent, evolutionarily conserved gene networks—many predating the plant-animal divergence—capable of identifying candidate disease genes.