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Computational searches for missing orthologs: the case of S100A12 in mice
Georg Fuellen1, Wolfgang Nacken, Clemens Sorg
1Integrated Functional Genomics, IZKF, Department of Medicine, University of Münster, Münster, Germany. fuellen@uni-muenster.de
Abstract:
The interaction of the Ca2+-binding protein S100A12 with RAGE (receptor of advanced glycation endproducts) has been considered as a novel proinflammatory axis, since blockage of RAGE/S100A12 ligation suppresses chronic cellular activation and tissue injury in mouse models. However, the existence of a murine S100A12 ortholog is unknown. Because experimental approaches failed to identify it, we started an analysis of gene locus evolution. Human S100A12 is localized in the S100 gene cluster between S100A8 and S100A9, which are neighbors in both mouse and human. Confirming identical gene order, we found a DNA region between the murine S100A8 and S100A9 genes that is 60.9% identical to a region of the human S100A12 gene, including the first exon. Instead of the second and third exon, we found homology to a region close to the human S100A9 locus. To exclude a murine S100A12 ortholog elsewhere in the genome, we used human S100A12 as query for TBlastN homology searches. The matches were either too short, or identity was too low, or they could clearly be identified as distinct S100 genes. Obviously, an S100A12 ortholog is neither present in mouse nor rat, indicating that S100A12 has been lost during rodent evolution, probably due to a deletion.
Insights
The S100A12 protein, crucial in inflammation, lacks a direct ortholog in mice and rats. This suggests S100A12 was lost during rodent evolution, impacting studies on the RAGE/S100A12 inflammatory axis.
Area of Science:
- Evolutionary biology
- Genomics
- Immunology
Background:
- The S100A12 protein interacts with RAGE (receptor of advanced glycation endproducts), forming a proinflammatory axis.
- Blocking this interaction reduces inflammation and tissue damage in mouse models.
Purpose of the Study:
- To investigate the existence of a murine S100A12 ortholog.
- To understand the evolutionary history of the S100A12 gene.
Main Methods:
- Comparative genomics analysis of the S100 gene cluster in humans and rodents.
- TBlastN homology searches using human S100A12 sequence.
- Analysis of gene locus evolution and sequence identity.
Main Results:
- A DNA region with partial homology to human S100A12 (first exon) was found between murine S100A8 and S100A9 genes.
- No clear S100A12 ortholog was identified in mouse or rat genomes via homology searches.
- Homology suggested potential gene deletion during rodent evolution.
Conclusions:
- A direct S100A12 ortholog is absent in rodents.
- S100A12 likely underwent deletion during rodent evolution.
- This finding necessitates re-evaluation of mouse models studying the RAGE/S100A12 axis.
