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

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.

Fig. 1.

The quartile plots of sequence divergence [d_N (a) and d_S (b)] and expression-profile divergence [ExonArray (c) and GeneAtlas v2 (d)] between human and mouse one-to-one orthologous genes. Values of upper quartile, median, and lower quartile are indicated in each box. The bars indicate semiquartile ranges. H and M indicate human and mouse, respectively, and the subscripts e, n, and a indicate essential, nonessential, and any genes, respectively. The P vales are determined by two-tailed Mann–Whitney U tests.

Fig. 2.

Variation of branch-specific d_N/d_S values among the five branches (marked a to e) that connect human and mouse in the mammalian phylogeny. The branch lengths are not drawn to scale. The d_N/d_S values for branches d and e have been adjusted to correct for the intrinsically low d_N/d_S in rodents (see Methods).