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VeriKine-HS Human IFN-Beta
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© The Rockefeller University Press, 0022-1007/1998/1/59/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 1, January 5, 1998 59-70

Article

Somatic Hypermutation Introduces Insertions and Deletions into Immunoglobulin V Genes

Patrick C. Wilson*,{ddagger}, Odette de Bouteiller§, Yong-Jun Liu§, Kathleen Potter*, Jacques Banchereau||, J. Donald Capra*,{ddagger}, and Virginia Pascual*

From the * Molecular Immunology Center, Department of Microbiology, University of Texas Southwestern Medical Center at Dallas, Texas 75235-9140; the {ddagger} Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104; § Schering-Plough Laboratory for Immunological Research, Dardilly, France; and || Baylor Institute for Immunological Research, Dallas, Texas 75235

During a germinal center reaction, random mutations are introduced into immunoglobulin V genes to increase the affinity of antibody molecules and to further diversify the B cell repertoire. Antigen-directed selection of B cell clones that generate high affinity surface Ig results in the affinity maturation of the antibody response. The mutations of Ig genes are typically basepair substitutions, although DNA insertions and deletions have been reported to occur at a low frequency. In this study, we describe five insertion and four deletion events in otherwise somatically mutated VH gene cDNA molecules. Two of these insertions and all four deletions were obtained through the sequencing of 395 cDNA clones (~110,000 nucleotides) from CD38+IgD– germinal center, and CD38–IgD– memory B cell populations from a single human tonsil. No germline genes that could have encoded these six cDNA clones were found after an extensive characterization of the genomic VH4 repertoire of the tonsil donor. These six insertions or deletions and three additional insertion events isolated from other sources occurred as triplets or multiples thereof, leaving the transcripts in frame. Additionally, 8 of 9 of these events occurred in the CDR1 or CDR2, following a pattern consistent with selection, and making it unlikely that these events were artifacts of the experimental system. The lack of similar instances in unmutated IgD+CD38– follicular mantle cDNA clones statistically associates these events to the somatic hypermutation process (P = 0.014). Close scrutiny of the 9 insertion/deletion events reported here, and of 25 additional insertions or deletions collected from the literature, suggest that secondary structural elements in the DNA sequences capable of producing loop intermediates may be a prerequisite in most instances. Furthermore, these events most frequently involve sequence motifs resembling known intrinsic hotspots of somatic hypermutation. These insertion/deletion events are consistent with models of somatic hypermutation involving an unstable polymerase enzyme complex lacking proofreading capabilities, and suggest a downregulation or alteration of DNA repair at the V locus during the hypermutation process.

Address correspondence to Dr. Virginia Pascual, Molecular Immunology Center, Department of Microbiology, UT Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, Texas 75235-9140. Phone: 214-648-1918; Fax: 214-648-1915; E-mail: vpascu{at}mednet.swmed.edu

1 Abbreviations used in this paper: FM, follicular mantle; FW, framework; GC, germinal center.


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