Recombination activating gene 1 (Rag1) in zebrafish and shark

Schluter

Proc. Natl. Acad. Sci. U.S.A.

et al. 1996

112

The rearrangement of antibody and T-cell receptor gene segments is indispensable to the vertebrate immune response. All extant jawed vertebrates can rearrange these gene segments. This ability is conferred by the recombination activating genes I and II (RAG I and RAG II). To elucidate their origin and function, the cDNA encoding RAG I from a member of the most ancient class of extant gnathostomes, the Carcharhine sharks, was characterized. Homology domains identified within shark RAG I prompted sequence comparison analyses that suggested similarity of the RAG I and II genes, respectively, to the integrase family genes and integration host factor genes of the bacterial site-specific recombination system. Thus, the apparent explosive evolution (or "big bang") of the ancestral immune system may have been initiated by a transfer of microbial site-specific recombinases.The characteristic immune response of vertebrates involves the production of immunoglobulin light and heavy chains, the capacity to generate diverse variable region sequences, and mechanisms to rearrange gene segments during development. These multiple mechanisms generate an immune response with the ability to recognize a number of potential antigens vastly greater than the number of genomic genes in an individual organism (1-5). Immunoglobulin light chains (6-8), heavy chains (6, 9-13), and homologs of T-cell receptors (14) occur in the most primitive extant gnathostomes-i.e., the chondrichthyes, an anciently evolved group that includes sharks, rays, and chimeras. These essential molecules of the vertebrate immune system have not yet been detected in vertebrate species more primitive than chondrichthyes, or in lower deuterostomes or protostomes (3-5, 13, 15). The recombination activating genes (RAG I and RAG II) are both critical for the rearrangement of immunoglobulin gene segments in T and B cells (16)(17)(18). To determine whether the mechanism for gene rearrangement in a primitive gnathastome, the bull shark, Carcharhinus leucas, was comparable to that seen in higher vertebrates, we isolated and analyzed a cDNA clone specifying the complete shark homolog of the RAG I gene. The mechanism of RAG function has not yet been established in any organism or in vitro system. What is known, however, is that both RAG I and RAG II are required for recognition and manipulation of DNA segments involved in generating immune diversity (16,17,19). We hypothesized that the comparison between the RAG I genes of two different species having an ancestral divergence of >400 million years would provide insight into the relationships of the functional domains of the RAG I protein and functional domains of other proteins known to recognize DNA sequences and modify DNA structure.Here we report that the shark RAG I homolog is strongly related to the mammalian prototype and consists of segments showing various degrees of identity to the mammalian gene product. Moreover, detection of homology to enzymes known to affect DNA processing provides a bridge between the vert...

Section: Resultsmentioning

confidence: 73%

Primordial emergence of the recombination activating gene 1 (RAG1): sequence of the complete shark gene indicates homology to microbial integrases.

Schluter

Proc. Natl. Acad. Sci. U.S.A.

et al. 1996

112

Proc. Natl. Acad. Sci. U.S.A.

“…Cartilaginous fish are the oldest animals having an adaptive immune system centered on rearranging antigen receptors. They have all four types of TcR (␣, ␤, ␥, ␦) (1), three Ig isotypes [IgM (2,3), IgW (4), and IgNAR (new antigen receptor) (5)], the recombination-activating gene recombinase (6), and polymorphic MHC genes (7,8). Studies of modern sharks may shed light on the origins of adaptive immunity (9).…”

Section: Cartilaginous Fish ͉ Evolution ͉ ␥͞␦ T Cells ͉ T Cell Receptmentioning

confidence: 99%

“…Genes encoding the same subfamilies of NAR-TcRV and TcR␦V domains are always found in the same RNA transcripts (e.g., NTV1 is only found in transcripts 5Ј of TRDV1). Alignment of four TcR␦V subfamilies that support NAR-TcRV (families 1-4) with typical ␦V subfamilies (families [5][6][7][8] shows the supporting ␦V domains to lack leader peptides and share a cysteine residue in CDR1 (Fig. 1D).…”

Section: Race Pcr Reveals a Nar Domainmentioning

confidence: 99%

An evolutionarily mobile antigen receptor variable region gene: Doubly rearranging NAR-TcR genes in sharks

Criscitiello

Saltis

Flajnik

2006

105

Distinctive Ig and T cell receptor (TcR) chains define the two major lineages of vertebrate lymphocyte yet similarly recognize antigen with a single, membrane-distal variable (V) domain. Here we describe the first antigen receptor chain that employs two V domains, which are generated by separate VDJ gene rearrangement events. These molecules have specialized ''supportive'' TcR␦V domains membrane-proximal to domains with most similarity to IgNAR V. The ancestral NAR V gene encoding this domain is hypothesized to have recombined with the TRD locus in a cartilaginous fish ancestor >200 million years ago and encodes the first V domain shown to be used in both Igs and TcRs. Furthermore, these data support the view that ␥͞␦ TcRs have for long used structural conformations recognizing free antigen.cartilaginous fish ͉ evolution ͉ ␥͞␦ T cells ͉ T cell receptor ͉ V(D)J rearrangement

“…Specifically, RAG1 has been identified in mammals, avians, amphibians, ray-finned fish, and cartilaginous fish (5). Shared regions of RAG1 in sandbar shark and zebrafish (Danio rerio) as well as in other higher vertebrates reveal high degrees of amino acid identity (158,159). RAG2 is somewhat less conserved phylogenetically than is RAG1 (160), but RAG1 and RAG2 are found in the same relative close proximity in lower vertebrates as in mammals (161).…”

Section: Genes Affecting Differentiation Of Lymphocytes and The Genermentioning

confidence: 99%

Evolution of Antigen Binding Receptors

Litman

Anderson

Rast

1999

Annu. Rev. Immunol.

293

197