In vivo transposition mediated by V(D)J recombinase in human T lymphocytes

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Abstract
The rearrangement of immunoglobulin (Ig) and T‐cell receptor (TCR) genes in lymphocytes by V(D)J recombinase is essential for immunological diversity in humans. These DNA rearrangements involve cleavage by the RAG1 and RAG2 (RAG1/2) recombinase enzymes at recombination signal sequences (RSS). This reaction generates two products, cleaved signal ends and coding ends. Coding ends are ligated by non‐homologous end‐joining proteins to form a functional Ig or TCR gene product, while the signal ends form a signal joint. In vitro studies have demonstrated that RAG1/2 are capable of mediating the transposition of cleaved signal ends into non‐specific sites of a target DNA molecule. However, to date, in vivo transposition of signal ends has not been demonstrated. We present evidence of in vivo inter‐chromosomal transposition in humans mediated by V(D)J recombinase. T‐cell isolates were shown to contain TCRα signal ends from chromosome 14 inserted into the X‐linked hypo xanthine–guanine phosphoribosyl transferase locus, resulting in gene inactivation. These findings implicate V(D)J recombinase‐mediated transposition as a mutagenic mechanism capable of deleterious genetic rearrangements in humans.