Joining of Immunoglobulin Heavy Chain Gene Segments: Implications from a Chromosome with Evidence of Three D-JH Fusions

Abstract

A chromosomal segment with a unique structure around the immunoglobulin heavy chain joining region (JH) has been molecularly cloned from an Abelson murine leukemia virus-transformed cell line. Attached to JH3 in the cloned DNA, in inverted sequence, is the DNA from JH1 to the JH2 recognition sequence. The inverted segment is attached at its other end to the 5' recognition sequence of a diversity segment (D). To form this structure, three joining events must have occurred on the same chromosome. One of these events could have been a normal D-JH joining but the others must have been irregular events including ones that result in inversions. One of the joining events left fused recognition elements from JH2 and a D whose sequence shows that, during joining, reciprocal joinings of the recognition elements must occur to fuse the heptameric elements back to back. Because joined D and JH undergo deletion of terminal coding sequence during recombination but the joined heptameric recognition sequences do not contain the deleted sequence, joining must be a nonreciprocal event. Also, extra nucleotides are inserted between D and JH as part of the joining process; it is suggested that this added sequence is a product of the activity of terminal deoxynucleotidyltransferase at the D/JH (and probably the VH/D) joints and that it represents a new element of heavy chain gene structure, the N region.