The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/12/2151/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 11, December 7, 1998 2151-2162

Articles

The Complete Nucleotide Sequence of the Human Immunoglobulin Heavy Chain Variable Region Locus

Fumihiko Matsuda*, Kazuo Ishii*, Patrice Bourvagnet{ddagger}, Kei-ichi Kuma§, Hidenori Hayashida||, Takashi Miyata§, and Tasuku Honjo*

From the * Department of Medical Chemistry, Kyoto University Graduate School of Medicine, Kyoto 60601, Japan; {ddagger} Centre National de la Recherche Scientifique Institute National de la Santé et Recherche Medicale, Montpellier 34033, France; § Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 60601, Japan; and || Statistics and Analysis of Information, Nara Medical University, Nara 634, Japan

The complete nucleotide sequence of the 957-kb DNA of the human immunoglobulin heavy chain variable (VH) region locus was determined and 43 novel VH segments were identified. The region contains 123 VH segments classifiable into seven different families, of which 79 are pseudogenes. Of the 44 VH segments with an open reading frame, 39 are expressed as heavy chain proteins and 1 as mRNA, while the remaining 4 are not found in immunoglobulin cDNAs. Combinatorial diversity of VH region was calculated to be ~6,000. Conservation of the promoter and recombination signal sequences was observed to be higher in functional VH segments than in pseudogenes. Phylogenetic analysis of 114 VH segments clearly showed clustering of the VH segments of each family. However, an independent branch in the tree contained a single VH, V4-44.1P, sharing similar levels of homology to human VH families and to those of other vertebrates. Comparison between different copies of homologous units that appear repeatedly across the locus clearly demonstrates that dynamic DNA reorganization of the locus took place at least eight times between 133 and 10 million years ago. One nonimmunoglobulin gene of unknown function was identified in the intergenic region.

Key Words: immunoglobulin gene • physical map • antibody repertoire • phylogenetic tree • DNA duplication

Address correspondence to Tasuku Honjo, Department of Medical Chemistry, Kyoto University Graduate School of Medicine, Yoshida, Sakyo-ku, Kyoto 60601, Japan. Phone: 81-75-753-4371; Fax: 81-75-753-4388; E-mail: honjo{at}mfour.med.kyoto-u.ac.jp

F. Matsuda's current address is Centre National de Genotypage, BP191-2, rue Geston Cremieux, 91000 Evry Cedex, France. K. Ishii's current address is JST Laboratory, Kitasato University Faculty of Science, Kitasato 1-15-1, Sagamihara 228-8555, Japan.

1 Abbreviations used in this paper: Mb, megabase; ORF, open reading frame; RSS, recombination signal sequences; YAC, yeast artificial chromosome.


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