Hozumi & Tonegawa

Hozumi & Tonegawa - Proc. Natl. Acad. Sci. USA Vol....

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Proc. Natl. Acad. Sci. USA Vol. 73, No. 10, pp. 3628-3632, October 1976 Genetics Evidence for somatic rearrangement of immunoglobulin genes coding for variable and constant regions (K-chain mRNA/restriction enzymes/RNA*DNA hybridization) NOBUMICHI HOZUMI AND SUSUMU TONEGAWA Basel Institute for Immunology, 487, Grenzacherstrasse, CH-4058 Basel, Switzerland Communicated by N. K. Jerne, July 2, 1976 ABSTRACT A high-molecular-weight DNA from Balb/c mouse early embryo or from MOPC 321 plasmacytoma (a K- chain producer) was digested to completion with Bacillus amyloliquefaciens strain H restriction enzyme (BamH I). The resulting DNA fragments were fractionated according to size in preparative agarose gel electrophoresis. DNA fragments carrying gene sequences coding for the variable or constant region of K chains were detected by hybridization with purified, 12SI-labeled, whole MOPC 321 K mRNA and with its 3'-end half. The pattern of hybridization was completely different in the genomes of embryo cells and of the plasmacytoma. The pattern of embryo DNA showed two components, one of which (mo- lecular weight = 6.0 million) hybridized with C-gene sequences and the other (molecular weight = 3.9 million) with V-gene se- quences. The pattern of the tumor DNA showed a single com- ponent that hybridized with both V-gene and C-gene sequences and that is smaller (molecular weight = 2.4 million) than either of the components in embryo DNA. The results were interpreted to mean that the VK and CK genes, which are some distance away from each other in the embryo cells, are joined to form a con- tiguous polynucleotide stretch during differentiation of lym- ph~c~es. Such joining occurs in both of the homologous chro- mosomes. Relevance of these findings with respect to models for V-C gene joining, activation of a specific Vk.gene, and allelic exclusion in immunoglobulin gene loci is discussed. Both light and heavy chains of immunoglobulin molecules consist of two regions: the variable region (V region) and the constant region (C region) (1, 2). Uniqueness (i.e., one copy per haploid genome) of the genetic material coding for C region ("C gene") has been conjectured from normal Mendelian seg- regation of allotypic markers (3). Nucleic acid hybridization studies have confirmed this notion (4-10). Hybridization studies have also demonstrated that a group of closely related V regions are somatically generated from a few, conceivably even a single, germline gene(s) (V gene) (4-6). They did not, however, give us any reliable estimate of the total number of germ line V genes. However, given the enormous diversity of V regions, the existence of multiple germ line V genes seems likely. If this is so, a problem arises: how is the information in the V and C genes integrated to generate a contiguous polypeptide chain? Since V- and C-gene sequences exist in a single mRNA molecule as a contiguous stretch (11), such integration must take place at either the DNA or the RNA level. Integration at the
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This note was uploaded on 03/09/2010 for the course BIO 380 taught by Professor Henson during the Spring '10 term at Dickinson.

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Hozumi & Tonegawa - Proc. Natl. Acad. Sci. USA Vol....

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