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Partitioning of Rearranged Ig Genes by Mutation Analysis Demonstrates D-D Fusion and V Gene Replacement in the Expressed Human Repertoire¹

Andrew M. Collins^2,*, Masashi Ikutani^*, Daniela Puiu, Gregory A. Buck, Aradhita Nadkarni^* and Bruno Gaeta^*

^* School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia; and Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, VA 23284

The accurate partitioning of Ig H chain V_HDJ_H junctions and L chain V_LJ_L junctions is problematic. We have developed a statistical approach for the partitioning of such sequences, by analyzing the distribution of point mutations between a determined V gene segment and putative Ig regions. The establishment of objective criteria for the partitioning of sequences between V_H, D, and J_H gene segments has allowed us to more carefully analyze intervening putative nontemplated (N) nucleotides. An analysis of 225 IgM H chain sequences, with five or fewer V mutations, led to the alignment of 199 sequences. Only 5.0% of sequences lacked N nucleotides at the V_HD junction (N1), and 10.6% at the DJ_H junction (N2). Long N regions (>9 nt) were seen in 20.6% of N1 regions and 17.1% of N2 regions. Using a statistical analysis based upon known features of N addition, and mutation analysis, two of these N regions aligned with D gene segments, and a third aligned with an inverted D gene segment. Nine additional sequences included possible alignments with a second D segment. Four of the remaining 40 long N1 regions included 5' sequences having six or more matches to V gene end motifs, which may be the result of V gene replacement. Such sequences were not seen in long N2 regions. The long N regions frequently seen in the expressed repertoire of human Ig gene rearrangements can therefore only partly be explained by V gene replacement and D-D fusion.

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