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Published December 1981 | public
Journal Article

Antibody diversity: Somatic hypermutation of rearranged V_H genes


The immune response to phosphorylcholine in BALB/c mice has been well characterized. Amino acid sequence analyses of heavy-chain variable (V_H) regions from 19 myeloma and hybridoma immunoglobulins binding phosphorylcholine show that 10 are identical (the prototype T15 V_H sequence) and 9 are distinct variants differing by one to eight residues. A T15 V_H DNA probe was used to isolate four closely related members of the T15 V_H gene family, including one encoding the T15 V_H sequence, from a sperm genomic library. A comparison of the protein and germline V_H sequences suggested that most of the immune response to phosphorylcholine is derived from the T15 germline V_H gene segment. The variant heavy chains from the M167 and M603 α immunoglobulins differ in their V_H protein sequences from T15 by eight and three residues, respectively. We analyzed the somatic variability in and around the coding regions of these two variant V_H genes by comparing them with the corresponding regions of the appropriate germline gene segments. The somatic variation has three properties: it is extensive and is found in flanking as well as coding sequences (for example, at least 44 substitutions for the M167 sequence and 10 substitutions for the M603 sequence); in the coding regions, it includes many silent as well as replacement substitutions; and it is focal in nature and centered around the rearranged V_H genes. Although the mutations extend into the neighboring upstream and downstream flanking sequences, sequences approximately 5 kb upstream and downstream from the V_H genes show no substitutions. Moreover, the associated heavy-chain constant genes (C_α from both variant α genes are unaltered, indicating that a closely linked and coexpressed gene is unmutated. We conclude that this somatic variation is generated by a special hypermutational mechanism highly localized in its site of execution and highly restricted in its time of operation during B-cell development.

Additional Information

© 1981 by MIT. Received 18 August 1981, Revised 13 October 1981. We are grateful to Stephen Crews, Michael Steinmetz and Henry Huang for valuable advice and discussions. We would like to acknowledge the excellent technical help of Karyl Minard. We are indebted to Steve Crews, Henry Huang and Johanna Griffin for the gifts of cloned DNAs; Tim Hunkapiller for the generation of the computerized data acquisition center; and Bernita Larsh for preparation of the manuscript. This work was supported by grants from the National Institutes of Health and a National Research Service Award from the National institute of General Medical Sciences to S. K. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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