Organization, Structure, and Assembly of Immunoglobulin Heavy Chain Diversity DNA Segments

We have identified, cloned, and sequenced eight different DNA segments encoding the diversity (D) regions of mouse immunoglobulin heavy-chain genes. Like the two D segments previously characterized (16, 17), all eight D segments are flanked by characteristic heptamers and nonamers separated by 12-bp spacers. These 10 D segments, and several more D segments identified but not yet sequenced, can be classified into three families based on the extent of sequence homology. The SP2 family consists of nine highly homologous D segments that are all 17-bp long and clustered in a chromosomal region of approximately 60 kb. The FL16 family consists of up to four D segments, two of which were mapped in the 5' end region of the SP2-D cluster. The two FL16D segments are 23 and 17 bp long. The third, the Q52 family, is a single-member family of the 10-bp-long DQ52, located 700 bp 5' to the JH cluster. We argue that the D-region sequences of the majority of heavy chain genes arise from these germline D segments by various somatic mechanisms, including joining of multiple D segments. We present a specific model of D-D joining that does not violate the 12/23-bp spacer rule.