Evolutionary rewiring of regulatory networks contributes to phenotypic differences between human and mouse orthologous genes

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).

Lethal phenotypes in Mendelian disorders

“…When performing comparisons between mouse and human lethal genes, several considerations need to be taken into account: 1) RNA expression profiles, including differences in developmental gene expression may reflect physiological differences between these two organisms 60,61 . This is supported by evidence of evolutionary divergence in regulatory networks contributing to phenotypic differences 62,63 ; 2) molecular function and biological processes are likely to remain constant between different species while physiological relevance may differ 64 ; 3) based on that, we may want to consider essential functions instead of essential genes, and approaches based on projection over functional modules, e.g. pathways or networks, have already been implemented 56 ; 4) even within the same species, we may observe variability due to genetic background, e.g.…”

Genome-wide association studies of human and rat BMI converge on synapse, epigenome, and hormone signaling networks

“…Although many genes and cellular processes are similar between humans and other mammals, the mapping of orthologous genes is imperfect, and gene and protein interaction patterns can vary between species due to the rewiring of regulatory and protein-protein interaction networks. 33 , 77 , 78 For this reason, work is ongoing to generate independent molecular interaction networks for mammalian species, including mice, 79 rats, 80 and cattle. 81 Network rewiring of interactions also occurs in different tissues and cell types.…”

Integrated bioinformatics analysis of the transcription factor-mediated gene regulatory networks in the formation of spermatogonial stem cells

“…It has previously been shown that the roles of TFs in GRNs are almost identical between humans and mice ( Stergachis et al, 2014 ; Yue et al, 2014 ). Interestingly, Kim et al found that the rewiring of GRNs contributes to the phenotypic discrepancies that occur between humans and mice ( Ha et al, 2022 ).…”