Null mutations in human and mouse orthologs frequently result in different phenotypes
Open accessAbstract
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.
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Among 215 genes with rhLOF that have an exact 1:1 mouse:human ortholog, 52 had a lethal mouse phenotype reported on at least one genetic background.
“We examined 215 genes with rhLOF in our dataset that have an exact 1:1 mouse:human gene ortholog. From mouse gene knockout data there were 52 genes where a lethal mouse phenotype had been reported on at least one genetic background(10).”
From Health and population effects of rare gene knockouts in adult humans with related parents (2016) · cites this paper as [10]
Null mutations of orthologous genes can produce vastly different phenotypes across species.
“null mutations of orthologous genes can result in vastly different phenotypes across species (Liao and Zhang, 2008).”
From The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016) · cites this paper as Liao and Zhang, 2008
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- Authors
- Liao, B.-Y., & Zhang, J.
- Affiliations
- University of Michigan (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-05-13
- Volume
- 105
- Issue
- 19
- Pages
- 6987-6992
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2383943
- OpenAlex
- W2116609981
- Cited by
- 234
- References
- 54
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 8 · 2023: 3 · 2022: 10 · 2021: 13 · 2020: 9 · 2019: 18 · 2018: 13 · 2017: 7 · 2016: 14 · 2015: 21 · 2014: 16 · 2013: 12 · 2012: 19
- FWCI
- 11.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Stanford Bio-X
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- gene essentiality, orthologs, null mutations, human-mouse orthologs, adaptive evolution, life history evolution, comparative genomics, model organisms, gene function prediction
- MeSH terms
- Amino Acid Sequence, Animals, Gene Expression Regulation, Humans, Mutation, Phenotype, Phylogeny, Sequence Homology, Nucleic Acid, Software, Vacuoles, Evolution, Molecular, Genes, Essential, Gene Duplication, Mice
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