The variable lymphocyte receptors (VLRs) of jawless vertebrates such as lamprey and hagfish are composed of highly diverse modular leucine-rich repeats. Each lymphocyte assembles a unique VLR by rearrangement of the germline gene. In the lamprey genome, we identify here about 850 distinct cassettes encoding leucine-rich repeat modules that serve as sequence templates for the hypervariable VLR repertoires. The data indicate a gene conversion–like process in VLR diversification. Genomic analysis suggested a link between the VLR and platelet glycoprotein receptors. Lamprey lymphocytes express two putative deaminases of the AID-APOBEC family that may be involved in VLR diversification, as indicated by in vitro mutagenesis and recombination assays. Vertebrate acquired immunity could have therefore originated from lymphocyte receptor diversification by an ancestral AID-like DNA cytosine deaminase.
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We thank the Genome Sequencing Center at Washington University for public access to the lamprey genome sequences; E.R. Mardis for genomic DNA from the sea lamprey donor of the genome sequence project; S. Kozmin (National Institute of Environmental Health Sciences) for the E. coli Rosetta ung− strain, A. Lada (Saint Petersburg University in Russia) for helping measure PmCDA1-induction of recombination in yeast; and M.D. Cooper (University of Alabama at Birmingham), M.F. Flajnik (University of Maryland, Baltimore) and M. Diaz (National Institute of Environmental Health Sciences) for discussions. Supported by the National Library of Medicine–National Institutes of Health–Department of Health and Human Services Intramural Research Program (I.B.R., L.M.I. and L.A.) and the National Science Foundation (MCB-0614672 to Z.P.). This is contribution 07-165 from the Center of Marine Biotechnology.
The authors declare no competing financial interests.
Database of translated genomic VLRA cassettes and their sequence logos. (PDF 202 kb)
Database of translated genomic VLRB cassettes and their sequence logos. (PDF 198 kb)
The sea lamprey VLRA. (PDF 397 kb)
Database of 194 mature VLRA sequences aligned to the corresponding genomic cassettes. (PDF 196 kb)
Database of 636 mature VLRB sequences aligned to the corresponding genomic cassettes (as in Supplementary Fig. 4). (PDF 344 kb)
The sea lamprey cytosine deaminase genes. (PDF 329 kb)
Alignment of the AID-APOBEC family with members of the cytosine deaminase superfamily. (PDF 105 kb)
In vitro mutagenesis of beta-galactosidase by co-expressed PmCDA1. (PDF 87 kb)
Mutagenic effect of PmCDA1 expression in ung+ or ung− E. coli. (PDF 29 kb)
Spectra of spontaneous and PmCDA1-induced mutations: i) in lacZ in vitro, ii) in E. coli rpoB in vivo, and iii) in S. cerevisiae can1 in vivo. (PDF 36 kb)
Mutagenic effect of PmCDA1 expression in ung+ or ung− S. cerevisiae. (PDF 28 kb)
Induction of intragenic recombination in yeast diploids by PmCDA1. (PDF 39 kb)
Sequence and location of PCR primers. (PDF 18 kb)
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Rogozin, I., Iyer, L., Liang, L. et al. Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase. Nat Immunol 8, 647–656 (2007). https://doi.org/10.1038/ni1463
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