Open Access Open Badges Research article

The medaka novel immune-type receptor (NITR) gene clusters reveal an extraordinary degree of divergence in variable domains

Salil Desai1, Amy K Heffelfinger12, Timothy M Orcutt1, Gary W Litman345 and Jeffrey A Yoder12*

Author Affiliations

1 Department of Molecular Biomedical Sciences and Center for Comparative Medicine and Translational Research, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA

2 Immunology Program, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA

3 Department of Pediatrics, University of South Florida College of Medicine, 830 First Street South, St. Petersburg, FL 33701, USA

4 H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Avenue, Tampa, FL 33612, USA

5 Department of Molecular Genetics, All Children's Hospital, 801 Sixth Street South, St. Petersburg, FL 33701, USA

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BMC Evolutionary Biology 2008, 8:177  doi:10.1186/1471-2148-8-177

Published: 19 June 2008



Novel immune-type receptor (NITR) genes are members of diversified multigene families that are found in bony fish and encode type I transmembrane proteins containing one or two extracellular immunoglobulin (Ig) domains. The majority of NITRs can be classified as inhibitory receptors that possess cytoplasmic immunoreceptor tyrosine-based inhibition motifs (ITIMs). A much smaller number of NITRs can be classified as activating receptors by the lack of cytoplasmic ITIMs and presence of a positively charged residue within their transmembrane domain, which permits partnering with an activating adaptor protein.


Forty-four NITR genes in medaka (Oryzias latipes) are located in three gene clusters on chromosomes 10, 18 and 21 and can be organized into 24 families including inhibitory and activating forms. The particularly large dataset acquired in medaka makes direct comparison possible to another complete dataset acquired in zebrafish in which NITRs are localized in two clusters on different chromosomes. The two largest medaka NITR gene clusters share conserved synteny with the two zebrafish NITR gene clusters. Shared synteny between NITRs and CD8A/CD8B is limited but consistent with a potential common ancestry.


Comprehensive phylogenetic analyses between the complete datasets of NITRs from medaka and zebrafish indicate multiple species-specific expansions of different families of NITRs. The patterns of sequence variation among gene family members are consistent with recent birth-and-death events. Similar effects have been observed with mammalian immunoglobulin (Ig), T cell antigen receptor (TCR) and killer cell immunoglobulin-like receptor (KIR) genes. NITRs likely diverged along an independent pathway from that of the somatically rearranging antigen binding receptors but have undergone parallel evolution of V family diversity.