Key Points

Shark genomes harbor more TNFSF genes than any other vertebrate examined to date.

Most human TNFSFs had already diversified in the jawed vertebrate ancestor.

Our data challenge the notion that immune regulation in sharks is “primitive”.

Abstract

Cytokines of the TNF superfamily (TNFSF) control many immunological processes and are implicated in the etiology of many immune disorders and diseases. Despite their obvious biological importance, the TNFSF repertoires of many species remain poorly characterized. In this study, we perform detailed bioinformatic, phylogenetic, and syntenic analyses of five cartilaginous fish genomes to identify their TNFSF repertoires. Strikingly, we find that shark genomes harbor ∼30 TNFSF genes, more than any other vertebrate examined to date and substantially more than humans. This is due to better retention of the ancestral jawed vertebrate TNFSF repertoire than any other jawed vertebrate lineage, combined with lineage-specific gene family expansions. All human TNFSFs appear in shark genomes, except for lymphotoxin-α (LTA; TNFSF1) and TNF (TNFSF2), and CD70 (TNFSF7) and 4-1BBL (TNFSF9), which diverged by tandem duplications early in tetrapod and mammalian evolution, respectively. Although lacking one-to-one LTA and TNF orthologs, sharks have evolved lineage-specific clusters of LTA/TNF co-orthologs. Other key findings include the presence of two BAFF (TNFSF13B) genes along with orthologs of APRIL (TNFSF13) and BALM (TNFSF13C) in sharks, and that all cartilaginous fish genomes harbor an ∼400-million-year-old cluster of multiple FASLG (TNFSF6) orthologs. Finally, sharks have retained seven ancestral jawed vertebrate TNFSF genes lost in humans. Taken together, our data indicate that the jawed vertebrate ancestor possessed a much larger and diverse TNFSF repertoire than previously hypothesized and oppose the idea that the cartilaginous fish immune system is “primitive” compared with that of mammals.

Footnotes

This work was supported by the Royal Society Research Grant RG130789 awarded to H.D. R.P. was supported by a Ph.D. Studentship from the College of Life Sciences and Medicine, University of Aberdeen. A.K.R. was supported by a PhD Studentship from the Centre for Genome-Enabled Biology & Medicine, University of Aberdeen, and by Irish Research Council Government of Ireland Postdoctoral Fellowship GOIPD/2021/466.

The online version of this article contains supplemental material.

R.P., A.K.R., and H.D. conceived and designed the experiments; R.P., A.K.R., and F.K.B. performed the experiments; and A.K.R., R.P., and H.D. analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.

Abbreviations used in this article:

iBAFFintronless BAFFLTAlymphotoxin-αMinVarminimum varianceNCBINational Center for Biotechnology InformationTACETNF-α converting enzymeTNFRSFTNFR superfamilyTNFSFTNF superfamilyUFBOOTultrafast bootstrapReceived April 25, 2022.Accepted August 19, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.