A hyperconversion mechanism generates the chicken light chain preimmune repertoire

Reynaud, Claude‐Agnès; Anquez, Viviane; Grimal, Hélène; Weill, Jean‐Claude

doi:10.1016/0092-8674(87)90189-9

Cited by 656 publications

(478 citation statements)

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“…GENE CONVERSION, which until this discovery was an underappreciated mechanism of immunereceptor diversification, uses pseudogenes that are encoded upstream of the main gene loci to somatically change V regions in birds [19][20][21] (as well as in some mammals 22,23 ); the 'converted' loci can also be somatically hypermutated 24 . Given these differences in the organization and the mechanisms of somatic diversification between sharks and birds, which strongly indicate co-evolution of immunoglobulin heavy-and light-chain gene organization and diversification mechanisms 25 , it comes as little surprise that BCRs in other species also show lineage-dependent divergence of immunoglobulin-gene organization and diversification (FIG.…”

Section: An Overview Of Adaptive Immunity In Phylogenymentioning

confidence: 99%

“…In sharks, the ancestors of which diverged early in jawed-vertebrate phylogeny, BCRs are encoded by hundreds of independent immunoglobulin-gene loci 17 , some of which undergo RAG-dependent recombination and others of which are pre-joined in the germline and therefore do not undergo combinatorial joining or generate JUNCTIONAL VARIATION 18 . By contrast, in birds, which diverged more recently as a group than sharks, the immunoglobulin loci consist of single variable (V) and joining (J) elements (which together encode immunoglobulin light chains), and single V and J elements plus multiple diversity (D) elements (which together encode immunoglobulin heavy chains).GENE CONVERSION, which until this discovery was an underappreciated mechanism of immunereceptor diversification, uses pseudogenes that are encoded upstream of the main gene loci to somatically change V regions in birds [19][20][21] (as well as in some mammals 22,23 ); the 'converted' loci can also be somatically hypermutated 24 . Given these differences in the organization and the mechanisms of somatic diversification between sharks and birds, which strongly indicate co-evolution of immunoglobulin heavy-and light-chain gene organization and diversification mechanisms 25 , it comes as little surprise that BCRs in other species also show lineage-dependent divergence of immunoglobulin-gene organization and diversification (FIG.…”

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Reconstructing immune phylogeny: new perspectives

2005

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Numerous studies of the mammalian immune system have begun to uncover profound interrelationships, as well as fundamental differences, between the adaptive and innate systems of immune recognition. Coincident with these investigations, the increasing experimental accessibility of non-mammalian jawed vertebrates, jawless vertebrates, protochordates and invertebrates has provided intriguing new information regarding the likely patterns of emergence of immune-related molecules during metazoan phylogeny, as well as the evolution of alternative mechanisms for receptor diversification. Such findings blur traditional distinctions between adaptive and innate immunity and emphasize that, throughout evolution, the immune system has used a remarkably extensive variety of solutions to meet fundamentally similar requirements for host protection.The evolutionary development of the METAZOANS was associated with the diversification of a wide range of specialized cell-surface molecules that mediate key metabolic processes, as well as provide crucial contact interfaces and carry out a broad range of other essential functions. It is not unexpected that some of these molecules also came to function as barriers to pathogenic invasion and, in doing so, began to carry out dedicated innate immune protective functions. Whereas the simplest form of protection, barrier formation, is essentially mechanical in nature, relentless pressure from genetic variation in pathogens probably drove the evolution of such innate immune protective molecules towards diversification and, in parallel, towards integration of signalling pathways to regulate cellular responses to external stimulation. However, despite the sophistication that such innate immune mediators achieved over time, their biological complexity, by definition, would be limited by genome space, so with increasing complexity of body plan and/or increasing pathogen sophistication, they could be overwhelmed. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMore than 500 million years ago, a TRANSPOSITION event, probably involving a recombinationactivating gene (RAG)-bearing element, might have given rise to the predecessors of the rearranging antigen-binding receptors of the jawed vertebrates, which encompass the vertebrate radiations that extend from the cartilaginous fish through to humans. This is considered the defining point in the emergence of RAG-mediated (conventional) adaptive immunity 1,2 , which has evolved to create a mechanism for deriving almost limitless variation from very few genes. Studies in traditional and non-traditional animal models, such as sharks, bony fish and birds, have brought this event and its ramifications for host defence into sharper focus. We can now predict much about how these rearranging antigenbinding receptors probably arose, what alternative pathways of immune-receptor gene evolution have occurred, what relationships exist between B-and T-cell-mediated immunity and natural killer (NK)-cell function, how complex immune ...

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Section: An Overview Of Adaptive Immunity In Phylogenymentioning

confidence: 99%

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confidence: 99%

Reconstructing immune phylogeny: new perspectives

2005

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“…Mechanistically, both processes appear to be triggered by activation-induced deaminase (AID)-catalyzed deamination of deoxycytidine (dC) to deoxyuridine (dU) within the IgV gene [1][2][3][4][5][6]. Although gene conversion is presumably achieved by recombination-mediated repair of the resultant DNA lesion using proximal IgV pseudogenes [7], the precise mechanism remains obscure. Thus, the initial deamination will yield a deoxyuridine/deoxyguanosine (dU/dG) base pair, which is likely to be recognized by components of the mismatch repair pathway (since dU/ dG is a mismatch) as well as by components of the base excision repair pathway [with uracil-DNA glycosylase (UDG) recognizing dU as a non-canonical base in DNA] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Immunoglobulin gene conversion in chicken DT40 cells largely proceeds through an abasic site intermediate generated by excision of the uracil produced by AID‐mediated deoxycytidine deamination

Noia

Neuberger

2004

Eur J Immunol

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Diversification of the primary antibody repertoire in chickens is achieved by a gene conversion process that uses a set of immunoglobulin variable (IgV) pseudogenes as templates. Studies using the chicken DT40 B lymphoma cell line have shown that this gene conversion is dependent on activation-induced deaminase, which deaminates deoxycytidine to deoxyuridine in the IgV gene. The mechanism by which the resultant deoxyuridine/deoxyguanosine (dU/dG) mismatch acts to initiate the gene conversion process is unknown but likely involves either (i) recognition of the dU/dG pair by the mismatch repair complex or (ii) recognition of the dU itself by uracil-DNA glycosylase. To discriminate these possibilities, we have investigated the effects on IgV gene conversion of inhibiting uracil-DNA glycosylase. We find that such inhibition diminishes gene conversion, biasing instead towards point mutations. These results demonstrate that IgV gene conversion in DT40 cells is substantially dependent on uracil excision and implies that it proceeds by a pathway involving an abasic site, which could be acted upon by an apyrimidinic endonuclease to generate a DNA strand break facilitating the conversion process.

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“…This was first demonstrated for the chicken where only single functional V and J segments are present in the light and heavy chain gene loci. Diversity is introduced into the rearranged V(D)J segments by gene conversion using pseudo V genes as donors (Reynaud et al, 1987). Not only avian species, but also rabbits, cattle, swine, and horses use gene conversion for B-cell repertoire formation (Butler, 1998).…”

Section: Introductionmentioning

confidence: 99%