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Updated: Jun 15, 2026

Using Phylogenetic Analysis to Investigate Eukaryotic Gene Origin
Published on: August 14, 2018
Phylogenetic analysis of the MS4A and TMEM176 gene families
Jonathan Zuccolo1, Jeremy Bau, Sarah J Childs
1Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
Background:
The MS4A gene family in humans includes CD20 (MS4A1), FcRbeta (MS4A2), Htm4 (MS4A3), and at least 13 other syntenic genes encoding membrane proteins, most having characteristic tetraspanning topology. Expression of MS4A genes is variable in tissues throughout the body; however, several are limited to cells in the hematopoietic system where they have known roles in immune cell functions. Genes in the small TMEM176 group share significant sequence similarity with MS4A genes and there is evidence of immune function of at least one of the encoded proteins. In this study, we examined the evolutionary history of the MS4A/TMEM176 families as well as tissue expression of the phylogenetically earliest members, in order to investigate their possible origins in immune cells.
Principal Findings:
Orthologs of human MS4A genes were found only in mammals; however, MS4A gene homologs were found in most jawed vertebrates. TMEM176 genes were found only in mammals and bony fish. Several unusual MS4A genes having 2 or more tandem MS4A sequences were identified in the chicken (Gallus gallus) and early mammals (opossum, Monodelphis domestica and platypus, Ornithorhyncus anatinus). A large number of highly conserved MS4A and TMEM176 genes was found in zebrafish (Danio rerio). The most primitive organism identified to have MS4A genes was spiny dogfish (Squalus acanthus). Tissue expression of MS4A genes in S. acanthias and D. rerio showed no evidence of expression restricted to the hematopoietic system.
Conclusions/Significance:
Our findings suggest that MS4A genes first appeared in cartilaginous fish with expression outside of the immune system, and have since diversified in many species into their modern forms with expression and function in both immune and nonimmune cells.
Insights
The MS4A gene family originated in cartilaginous fish outside the immune system. These genes later evolved diverse immune and non-immune functions across species.
Area of Science:
- Genomics
- Evolutionary Biology
- Immunology
Background:
- The MS4A gene family, including CD20, comprises membrane proteins with varied tissue expression, notably in the hematopoietic system.
- The TMEM176 gene group shares similarities with MS4A genes, with some members implicated in immune functions.
- Understanding the evolutionary trajectory and early expression patterns of MS4A/TMEM176 genes may illuminate their origins in immune cells.
Purpose of the Study:
- To investigate the evolutionary history of the MS4A and TMEM176 gene families.
- To examine the tissue expression of the earliest MS4A gene members across different species.
- To explore the potential origins of MS4A genes within immune cell lineages.
Main Methods:
- Comparative genomics to identify orthologs and homologs of MS4A and TMEM176 genes across vertebrate species.
- Phylogenetic analysis to trace the evolutionary relationships of these gene families.
- Tissue expression analysis in primitive organisms like spiny dogfish and zebrafish.
Main Results:
- MS4A gene orthologs are exclusive to mammals, while homologs are found in most jawed vertebrates.
- TMEM176 genes are present in mammals and bony fish; unusual tandem MS4A gene structures were found in chickens and early mammals.
- MS4A genes were identified in spiny dogfish, the most primitive organism studied, with expression outside the hematopoietic system in both spiny dogfish and zebrafish.
Conclusions:
- MS4A genes likely emerged in cartilaginous fish with functions distinct from the immune system.
- Subsequent diversification led to modern MS4A genes with roles in both immune and non-immune cells.
- The evolutionary path suggests a gradual acquisition and specialization of immune functions within the MS4A gene family.
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