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EVOLUTION
Null mutations in human and mouse orthologs frequently result in different phenotypes

Ben-Yang Liao and Jianzhi Zhang^*

Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI 48109

Edited by David J. Lipman, National Institutes of Health, Bethesda, MD, and approved March 10, 2008 (received for review January 14, 2008)

Abstract

One-to-one orthologous genes of relatively closely related species are widely assumed to have similar functions and cause similar phenotypes when deleted from the genome. Although this assumption is the foundation of comparative genomics and the basis for the use of model organisms to study human biology and disease, its validity is known only from anecdotes rather than from systematic examination. Comparing documented phenotypes of null mutations in humans and mice, we find that >20% of human essential genes have nonessential mouse orthologs. These changes of gene essentiality appear to be associated with adaptive evolution at the protein-sequence, but not gene-expression, level. Proteins localized to the vacuole, a cellular compartment for waste management, are highly enriched among essentiality-changing genes. It is probable that the evolution of the prolonged life history in humans required enhanced waste management for proper cellular function until the time of reproduction, which rendered these vacuole proteins essential and generated selective pressures for their improvement. If our gene sample represents the entire genome, our results would mean frequent changes of phenotypic effects of one-to-one orthologous genes even between relatively closely related species, a possibility that should be considered in comparative genomic studies and in making cross-species inferences of gene function and phenotypic effect.

evolution | mammals | gene essentiality | vacuole

Author contributions: B.-Y.L. and J.Z. designed research; B.-Y.L. performed research; B.-Y.L. and J.Z. analyzed data; and B.-Y.L. and J.Z. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

*To whom correspondence should be addressed at: Department of Ecology and Evolutionary Biology, University of Michigan, 1075 Natural Science Building, 830 North University Avenue, Ann Arbor, MI 48109. E-mail: jianzhi{at}umich.edu

© 2008 by The National Academy of Sciences of the USA

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