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Divergence of non-coding regulatory elements explains gene-phenotype differences between human and mouse orthologous genes
 Authors and Affiliations  Authors and Affiliations
Seong Kyu Han1, Donghyo Kim1, Heetak Lee1, Inhae Kim1 and Sanguk Kim1, *
1Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Korea
*Correspondence should be addressed to: Sanguk Kim, Ph.D., Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Korea
Abstract
Mice have been widely used as a model organism to investigate human gene-phenotype relationships based on a conjecture that orthologous genes generally perform similar functions and are associated with similar phenotypes. However, phenotypes associated with orthologous genes often turn out to be quite different between human and mouse. Herein, we devised a method to quantitatively compare phenotypes annotations associated with mouse models and human. Using semantic similarity comparisons, we identified orthologous genes with different phenotype annotations, of which the similarity score is on a par with that of random gene pairs. Analysis of sequence evolution and transcriptomic changes revealed that orthologous genes with phenotypic differences are correlated with changes in non-coding regulatory elements and tissue-specific expression profiles rather than changes in protein-coding sequences. To map accurate gene-phenotype relationships using model organisms, we propose that careful consideration of the evolutionary divergence of non-coding regulatory elements and transcriptomic profiles is essential.
Keywords: Gene-phenotype relationship, Mouse model, Orthologous gene, non-coding regulatory element, transcriptomic profile
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