Yuko Ohta, PhD

6)        Uffe Hellsten, Richard M. Harland, Michael J. Gilchrist,  et al., , Yuko Ohta, et al., and

Daniel S. Rokhsar. 2010. The Genome of the Western Clawed Frog Xenopus tropicalis. Science 328: 633-636.

7)        Ohta Y, Flajnik M. 2006. IgD, like IgM, is a primordial immunoglobulin class perpetuated in most jawed vertebrates. Proc Natl Acad Sci U S A 103(28):10723-8.

8)        Yuko Ohta, Churchill McKinney, and Martin Flajnik. 2002. Proteasome, TAP, and class I genes in the nurse shark Ginglymostoma cirratum: evidence for a stable "class I region" and MHC haplotype lineages. J Immunol. 168:771-781.

9)        Ohta Y, Okamura K, McKinney EC, Bartl S, Hashimoto K, and Flajnik MF. 2000. Primitive synteny of vertebrate major histocompatibility complex class I and class II genes. Proc. Natl. Acad. Sci. 97(9):4712-4717.

10)      Bartl S, Baish MA, Flajnik MF, and Ohta Y. 1997. Identification of class I genes in cartilaginous fish, the most ancient group of vertebrates displaying in adaptive immune response. J. Immunol.159:6097-6104.

11)      Haire RN, Ohta Y, Strong SJ, Litman RT, Liu Y, Prchal JT, Cooper MD, and Litman GW. 1997. Unusual patterns of exon skipping in Bruton's tyrosine kinase are associated with mutations involving the intron 17 3' splice site. Am. J. Hum. Genet. 60:798-807.

12)      Ohta Y, Haire RN, Litman RT, Fu SM, Nelson RP, Kratz J, Kornfeld S, de la Morena M, Good RA, and Litman GW. 1994. Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied linked agammaglobulinemia. Proc. Natl. Acad. Sci. 91:9062-9066.

13)      Taketoshi Kato, Yuko Ohta, Yasuko Suzumura, Kohfuku Kohda, Hiroshi Kimoto, and Yutaka Kawazoe. 1988. Antitumor activity of the neutrophil-selective toxicity of busulfan analogs in mice. Jpn. J. Cancer Res. 79:1048-1053.

Current research interests

1) Comparative immunogenomics:

The major histocompatibility complex (MHC) is a gene-rich genetic region that plays a central role in antigen-specific adaptive immunity. The MHC has been mapped in many species. Such comparative analysis have provided much insight into the architecture of the ‘proto-MHC’,  which has shed light on the evolution of the immune system and changed our view of the mammalian immune system.

I have been mapping MHC loci in sharks and the amphibian Xenopus, gradually inferring the ancestral ‘proto MHC’ regions. MHC genes are generally highly polymorphic; they have been frequently used for population genetics studies. We previously identified and typed maternal and paternal alleles for MHC genes using several wild-caught shark families^REF1. We have shown that the ‘proto MHC’ includes other immune-related genes such as antigen receptors, natural killer (NK) receptors, costimulatory molecules of both the immunoglobulin superfamily (IgSF) and tumor necrosis factor (TNF) superfamilies, and cathepsins, conforming in total to a ‘pre-adaptive immune complex (PIC).’ Much progress has been made using genomes from various cartilaginous fish and Xenopus species. Below, I provide a brief description of our animal models and ongoing projects.

Sharks: Sharks belong to the oldest jawed vertebrate taxon possessing adaptive immune genes similar to humans, including T cell receptor (TCR), immunoglobulin (Ig), and MHC. We previously reported the architectural similarity of human and shark MHCs^REF1,2 and further revealed the primordial linkage of the beta-2 microglobulin (b2M) gene to the MHC^REF3. b2M is clearly related to class I and class II MHC molecules, and b2M has been assumed to be linked to the MHC. However b2M is encoded outside the MHC in all examined species from bony fish to mammals, and probably was translocated from its original location within the MHC early in vertebrate evolution. Our study satisfies the long-held conjecture that b2M was linked to the ‘proto MHC.’ Furthermore, the apparent stability of the shark genome further suggests the presence of the other genes predicted to have had a primordial association with the proto MHC or “PIC.”

Xenopus:The amphibian Xenopus has been a model organism for studies in developmental biology for many decades. Evolutionarily, Xenopus is one of the high connectivity animals linking mammals to lower vertebrate taxa, and they indeed display a transitional immune system. In addition, animals with different levels of ploidy (2n-12n) exist among Xenopus species and thus it is a unique animal model to study genome evolution. Thus far, the diploid Xenopus tropicalis and the tetraploid X. laevis genomes have been sequenced. Comparative genomic analysis revealed that, in contrast to teleost fish and birds, the genomic synteny of Xenopus is remarkably similar to that of human; yet, in some cases, apparent ancestral syntenies are found only in the Xenopus genome demonstrating that Xenopus is a useful genomic model to examine primordial synteny. From extensive in silico analysis, we uncovered the entire MHC architecture^REF4. Unexpectedly, we found natural killer (NK)-like receptors (XMIV) of the IgSF in the Xenopus MHC; in combination with analysis of MHC in other warm-blooded vertebrate species, NK receptors are assumed to have been present in the proto MHC. 

2) Characterization of novel genes containing V- and C1-type immunoglobulin superfamily (IgSF) domains in lower vertebrates:

We have been most interested in immune genes that belong to the so-called “VJ-type” variable (V) and the “C1-type” constant IgSF domains. Both domains are of special interest for the following reasons:  

The “VJ-type” domains resemble to the ancestral V that predated antigen receptors (Ig, TCR). We found two such genes (XMIV^REF4 and NKp30^REF5) from Xenopus that potentially serve as receptors for NK cells. Furthermore, our finding of NKp30 from shark revealed that NKp30 is to date the only evolutionarily conserved vertebrate NK receptor^REF5. 

The “C1-IgSF” domains appeared evolutionarily at the same time as the emergence of jawed vertebrates, since they are primarily found in the adaptive immune molecules (e.g. Ig, TCR, MHC). There are only a few other molecules, such as B7 family members, that contain C1-IgSF domains. We found the majority of the B7 costimulatory family members from Xenopus and sharks and revealed that B7 genes are derived from the common ancestor of molecules with C1 domains. Phylogenetic tree analysis revealed that some of the C1-IgSF domains, particularly those in B7H6, are distantly related to all the C1-IgSF domains present in adaptive immune molecules^REF5.

Origin of cellular immunity: It has been speculated that ancient “killer” cells, which predated NK cells and T cells, monitored the cell surface for modulation of self-molecules during infection. VJ-containing molecules, such as NKp30, are candidate receptors for such ancient “killer” cells. Later, the VJ- domains were likely combined with C1-IgSF domains to generate the precursor of antigen receptors (Ig, TCR). Furthermore, we revealed that NKp30 coevolves with its ligand, B7H6, which is a self-molecule that is upregulated under stress conditions. Therefore, the NKp30-B7H6 system resembles such an ancient “killer” cell system and we hypothesize that NKp30 might be a lynchpin to interrogate the evolutionarily origin of cellular immunity as well as the origin of antigen receptors. 

Member- The American Association of Immunologists (2010-present)

AAI Junior Faculty Travel Grant at 98^th AAI annual meeting (USA) (2011)