ArticleNucleic acids research2022
Evolutionary rewiring of regulatory networks contributes to phenotypic differences between human and mouse orthologous genes.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 18 citations in OpenAlex.
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- Quantifying pathway perturbations based on gene network rewiring in sepsis progression toward death or survival.Frontiers in bioinformatics · 2026Article
- Drug toxicity prediction based on genotype-phenotype differences between preclinical models and humans.EBioMedicine · 2025Article
- GETdb: A comprehensive database for genetic and evolutionary features of drug targets.Computational and structural biotechnology journal · 2024Article
- Nontraditional models as research tools: the road not taken.Trends in molecular medicine · 2024Review
- Computational strategies for cross-species knowledge transfer and translational biomedicine.ArXiv · 2024Article
- Lethal phenotypes in Mendelian disorders.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Lethal phenotypes in Mendelian disorders.medRxiv : the preprint server for health sciences · 2024Article
- Genome-wide association studies of human and rat BMI converge on synapse, epigenome, and hormone signaling networks.Cell reports · 2023Article
- Pan-glioma analyses reveal species- and tumor-specific regulation of neuron-glioma synapse genes by lncRNAs.Frontiers in genetics · 2023Article
- Development of bioinformatics and multi-omics analyses in organoids.BMB reports · 2023Review
- Integrated bioinformatics analysis of the transcription factor-mediated gene regulatory networks in the formation of spermatogonial stem cells.Frontiers in physiology · 2022Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mouse models have been engineered to reveal the biological mechanisms of human diseases based on an assumption. The assumption is that orthologous genes underlie conserved phenotypes across species. However, genetically modified mouse orthologs of human genes do not often recapitulate human disease phenotypes which might be due to the molecular evolution of phenotypic differences across species from the time of the last common ancestor. Here, we systematically investigated the evolutionary divergence of regulatory relationships between transcription factors (TFs) and target genes in functional modules, and found that the rewiring of gene regulatory networks (GRNs) contributes to the phenotypic discrepancies that occur between humans and mice. We confirmed that the rewired regulatory networks of orthologous genes contain a higher proportion of species-specific regulatory elements. Additionally, we verified that the divergence of target gene expression levels, which was triggered by network rewiring, could lead to phenotypic differences. Taken together, a careful consideration of evolutionary divergence in regulatory networks could be a novel strategy to understand the failure or success of mouse models to mimic human diseases. To help interpret mouse phenotypes in human disease studies, we provide quantitative comparisons of gene expression profiles on our website (http://sbi.postech.ac.kr/w/RN).
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