Image: Wikimedia – Alberto Salguero Model organisms used in the study of human disease have, up until now, generally closely resembled the disease being studied but scientists in the US have described a new way of identifying other, less obvious, disease models. Although the functions of a particular protein are generally conserved at the molecular level, this is not necessarily true at the level of the organism and disruption of protein function can lead to radically different phenotypic outcomes in different species.
Orthologous phenotypes (phenologs) are defined as phenotypes related by the orthology of the associated genes in two organisms although the observed phenotypes may be very different, depending on the organism-specific role played by each set of genes. The team examined human disease-gene associations and gene-phenotype associations in mice, C. elegans and yeast, looking for overlaps. As well as correctly identifying many known mouse models of human disease, the analysis also identified completely new phenologs. Two processes that were found to share 5 genes were abnormal angiogenesis in mutant mice and reduced growth rate of yeast deletion strains in the presence of the cholesterol-lowering drug, lovastatin. The set of genes regulates cell wall stress and biogenesis in yeast cells and regulates proper formation and maintenance of blood vessels in mice, suggesting that budding yeast – whilst obviously lacking blood vessels – could potentially model mammalian angiogenesis. The model predicts that some of the other genes associated with lovastatin sensitivity in yeast should also be involved in angiogenesis, and the team were able to identify a previously unrecognised role for the gene SOX13 in angiogenesis.
To test whether other very distantly related species could serve as human disease models, the team looked for phenologs between the mustard plant, Arabidopsis thaliana, and fungi and animals. The human-plant phenologs suggested associations between specific plant mutational phenotypes and a variety of human diseases, including cancers, peroxisomal disorders and birth defects. One striking plant-human phenolog linked plant gravitational growth responses to Waardenburg syndrome.
In spite of the extremely different phenotypes, phenologs can identify functionally coherent gene sets that predate the divergence of plants and animals and lead to novel, non-obvious models of human disease.
The study is published in PNAS.