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Multiple divergent haplotypes express completely distinct sets of class I MHC genes in zebrafish

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Abstract

The zebrafish is an important animal model for stem cell biology, cancer, and immunology research. Histocompatibility represents a key intersection of these disciplines; however, histocompatibility in zebrafish remains poorly understood. We examined a set of diverse zebrafish class I major histocompatibility complex (MHC) genes that segregate with specific haplotypes at chromosome 19, and for which donor-recipient matching has been shown to improve engraftment after hematopoietic transplantation. Using flanking gene polymorphisms, we identified six distinct chromosome 19 haplotypes. We describe several novel class I U lineage genes and characterize their sequence properties, expression, and haplotype distribution. Altogether, ten full-length zebrafish class I genes were analyzed, mhc1uba through mhc1uka. Expression data and sequence properties indicate that most are candidate classical genes. Several substitutions in putative peptide anchor residues, often shared with deduced MHC molecules from additional teleost species, suggest flexibility in antigen binding. All ten zebrafish class I genes were uniquely assigned among the six haplotypes, with dominant or codominant expression of one to three genes per haplotype. Interestingly, while the divergent MHC haplotypes display variable gene copy number and content, the different genes appear to have ancient origin, with extremely high levels of sequence diversity. Furthermore, haplotype variability extends beyond the MHC genes to include divergent forms of psmb8. The many disparate haplotypes at this locus therefore represent a remarkable form of genomic region configuration polymorphism. Defining the functional MHC genes within these divergent class I haplotypes in zebrafish will provide an important foundation for future studies in immunology and transplantation.

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Acknowledgments

We thank Leonard Zon for AB-derived zebrafish and Sergei Revskoy for clonal zebrafish. We are grateful to Aye Chen and Yi Zhou for sharing primers for haplotype determination. We thank Michael Peters, Wilfredo Marin, Jissy Cyriac, William Tian, William Buikema, and the University of Chicago sequencing core for technical assistance. We thank Xinan (Holly) Yang for help with statistical analyses. We also thank Hayley Dirscherl, Jeffrey Yoder, Erin Adams, Anita Chong, Derek Stemple, Amy Singer, and members of the de Jong laboratory for helpful discussion. This work was supported by grants from the NIDDK (K08DK074595 and R03DK091497), as well as funds from the University of Chicago Cancer Research Foundation Auxiliary Board.

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  1. Department of Pediatrics, Section of Hematology/Oncology, Knapp Center for Biomedical Discovery, University of Chicago, 900 E. 57th St., Chicago, IL, 60637, USA

    Sean C. McConnell, Anthony C. Restaino & Jill L. O. de Jong

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  1. Sean C. McConnell
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  2. Anthony C. Restaino
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  3. Jill L. O. de Jong
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Correspondence to Jill L. O. de Jong.

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McConnell, S.C., Restaino, A.C. & de Jong, J.L.O. Multiple divergent haplotypes express completely distinct sets of class I MHC genes in zebrafish. Immunogenetics 66, 199–213 (2014). https://doi.org/10.1007/s00251-013-0749-y

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