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Gene conversion in human rearranged immunoglobulin genes

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Abstract

Over the past 20 years, many DNA sequences have been published suggesting that all or part of the VH segment of a rearranged immunoglobulin gene may be replaced in vivo. Two different mechanisms appear to be operating. One of these is very similar to primary V(D)J recombination, involving the RAG proteins acting upon recombination signal sequences, and this has recently been proven to occur. Other sequences, many of which show partial VH replacements with no addition of untemplated nucleotides at the VH–VH joint, have been proposed to occur by an unusual RAG-mediated recombination with the formation of hybrid (coding-to-signal) joints. These appear to occur in cells already undergoing somatic hypermutation in which, some authors are convinced, RAG genes are silenced. We recently proposed that the latter type of VH replacement might occur by homologous recombination initiated by the activity of AID (activation-induced cytidine deaminase), which is essential for somatic hypermutation and gene conversion. The latter has been observed in other species, but not in human Ig genes, so far. In this paper, we present a new analysis of sequences published as examples of the second type of rearrangement. This not only shows that AID recognition motifs occur in recombination regions but also that some sequences show replacement of central sections by a sequence from another gene, similar to gene conversion in the immunoglobulin genes of other species. These observations support the proposal that this type of rearrangement is likely to be AID-mediated rather than RAG-mediated and is consistent with gene conversion.

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Notes

  1. R=A/G, Y=C/T, W=A/T, D=A/G/T, H=C/T/A.

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Acknowledgements

The authors wish to acknowledge the support of the Scottish Executive, Chief Scientist Office, Grant No. CZB/4/14 and Cancer Research UK, Grant No. 4327.

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  1. John M. Darlow

    Present address: National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland

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  1. Department of Immunology, Level 4, Glasgow Biomedical Research Centre, 120 University Place, Glasgow, G12 8TA, UK

    John M. Darlow & David I. Stott

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Correspondence to John M. Darlow.

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Darlow, J.M., Stott, D.I. Gene conversion in human rearranged immunoglobulin genes. Immunogenetics 58, 511–522 (2006). https://doi.org/10.1007/s00251-006-0113-6

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  • DOI: https://doi.org/10.1007/s00251-006-0113-6

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