The sequences of four embryonic mouse immunoglobulin VH genes have been compared. All genes end at codon 98 and code for a hydrophobic signal peptide of 19 residues interrupted at codon -4 by an intron of 83 base pairs. Substitutions occur in all gene segments but at a significantly higher frequency in the hypervariable regions. The data suggest an evolutionary basis for the diversity of immunoglobulin genes. Divergence resulted also in a termination codon in two of the genes, suggesting that part of the V gene repertoire cannot be expressed unless some correction mechanism is available.

The activation of the cellular oncogene c-mos in mouse plasmacytoma XRPC24 was found to result from the insertion of a 4.7-kilobase-pair cellular DNA element, within the cmos coding region. The element terminates on both sides with a direct repeat of around 335 nucleotides. The repeat as well as internal sequences of the element show strong homology to endogenous intracisternal A-particle (LAP) genes. The LAP genome integrated within c-mos in a headto-head (5' to 5') configuration. This juxtapositioned the LAP 5' long terminal repeat next to the bulk of the oncogene's coding region and shifted c-mos 5' coding and flanking sequences to a position further upstream. The significance of several aspects of this activation and transposition event is discussed.c-mos is a member of the family of cellular sequences, termed onc genes, which possess the potential to become malignant through incorporation into the genome of retroviruses (1) or by undergoing alterations within the cell (2). c-nos is the progenitor of the transforming information (v-mos) in Moloney murine sarcoma virus. The virus is presumably a recombinant between Moloney murine leukemia virus and the c-nos gene of BALB/ c mice (3, 4). c-and v-mos are composed of nearly identical sequences over their coding region, with the exception that cmos contains 21 additional codons at the 5' terminus, substituted in v-mos with 5 codons derived from viral helper sequences (5, 6). A Mr 37,000 protein identified within virus-infected cells (7) is encoded by the 374 codons of v-mos and presumably triggers cellular malignant transformation. No homologous protein coded by c-mos has been detected in normal cells.In a recent study (8) we described the rearrangement of the c-mos gene in mouse plasmacytoma XRPC24. Sequences from the 5' region of the gene, including 264 nucleotides of the presumed mos coding sequence as well as 5' flanking DNA, were substituted with a unique DNA. This rearrangement was accompanied by the appearance of mos transcripts in the tumor. Moreover, the molecularly cloned rearranged gene (termed rcmos), unlike its normal counterpart, induced transformed foci upon transfection into NIH/3T3 monolayers.More recently it was shown (9) that a 0.35-kilobase-pair (kbp) segment of the unique DNA, immediately adjacent to the junction point with c-mos sequences retained in rc-mos, had 88% sequence homology with the long terminal repeat (LTR) of an endogenous genetic element molecularly cloned from a library of mouse DNA (10). This element is a member of a family of highly reiterated endogenous mouse genes [intracisternal A particle (IAP) genes] homologous to the RNA of IAPs. The latter are noninfectious retrovirus-like structures found regularly in early mouse embryos (11-13) and present abundantly in every mouse plasmacytoma (14) and other mouse tumors (15).The association between an IAP LTR and the rearranged cellular mos was of considerable interest because it constituted one example of activation of a cellular oncogene by a mechanism involving relocat...

The organization and evolution of immunoglobulin variable region genes was studied by comparing human and mouse heavy chain variable region (VH) genes. We show that a VH gene subgroup constitutes a physically linked multigene family separated from another VH subgroup. We mapped the VHIII gene subgroup to be 3' to the VHII gene subgroup based on deletion of VH genes after V-D-J rearrangement. The results indicate that the human VHIII gene subgroup underwent a significant gene expansion as compared to the mouse VHIII subgroup. Amino acid sequence data indicate that human VHIII genes correspond to only a small subset of mouse VHIII genes. Human VHIII genes contain a shorter intron and are two codons shorter than most BALB/c mouse VHIII genes. The nature of nucleotide substitutions between VH genes within a species (human) is similar to that between genes of different species (human/mouse). Both contain approximately 50% silent substitutions.Both somatic and genetic ("germ line") factors operate in generating antibody diversity (1-3). The somatic processes probably act sequentially: first, by combinatorial joining of two or three gene segments, which is accompanied by junctional variation (4-6), and second, by somatic mutations, which take place after the switching process from IgM expression to other immunoglobulin classes (2,7,8). However, it is clear that the diversity of germ line heavy chain variable region and light chain variable region (VH and VL, respectively) genes is extensive and is accumulated throughout evolution (1, 9). Amino acid sequence data indicated that the variable regions of immunoglobulins can be divided into subgroups according to their extent of homology (10-13). A similar subdivision can be made on the level of the genes on the basis of cross hybridization of different V genes with various cDNA probes in which hybridization takes place with distinct sets of V genes (1, 14-17). Subgroups of genes defined by cross hybridization do not always correspond to subgroups defined by protein sequence (17), but in many cases-depending on the conditions of hybridization-there is a good correlation between the two (15).The evolution of multigene families like the V gene subgroups may lead to gene expansion or contraction (11,18), thereby modifying the germ line repertoire of V genes. Comparison of VH gene subgroups from different species may increase our understanding of the evolutionary factors operating in generating antibody diversity. We studied some aspects of the organization and evolution of the VHIII subgroup by comparing human and mouse VH genes. We show by deletion mapping that VHIII genes are located 3' to VHII genes on the mouse chromosome and that the two subgroups are not intermingled with each other. Our sequence analysis data of human VHIII genes suggest that they correspond to a particular subset of mouse VHIII genes. However, the VHIII gene subgroup in human contains significantly more genes than does VHIII in BALB/c mice. The sequence comparison also demonstrates that the pr...

We isolated and determined the sequences oftwo human germ-line heavy chain variable region (VH) genes and compared them with mouse VH genes. The The variable region of the immunoglobulin heavy chain is encoded in the germ line in three separate DNA segments: VH, DH, andJH (1-3). Three ofthe framework regions (FRs) and two of the complementarity-determining regions (CDRs) are included in the coding region of the VH segment whereas recombination between variable (V), diversity (D), and joining (J) segments is necessary to form the expressed VH gene. It is likely that there are several hundred VH gene segments organized in tandem with spacers of 8-15 kilobases (4-6). The multitude of V region amino acid sequences has been subdivided into subgroups that show a higher extent of homology and linkage between some amino acids along the chain (7-9). However, comparison of the amino acid sequences of mouse and human VH does not always allow the affiliation of V regions from the different species to homologous subgroups (10); the DNA sequences of the VH genes may provide a better tool for comparison of homologous subgroups in various species. Hybridization with VH DNA probes showed a correlation between the extent of cross-hybridization and VH gene subgroups (11). It VH families (11) and comparison of VH genes from different species will increase our understanding of the structural features that characterize a subgroup in coding and noncoding regions. We isolated human germ-line VH genes by cross-hybridization with mouse VHII genes (6). The DNA sequence shows that the human genes are homologous to human VHI (subgroup I), as defined by Kabat et al. (14) and we will refer to the human genes analyzed here as human VHII genes. The homology between mouse and human VHII genes is preserved in the size [84 base pairs (bp)] and also in the sequence ofthe intron present at codon 4. Another VH gene subgroup (VHIII) contains a longer intron (102 bp) in both mouse and human (11). The homology in both intron and framework codons between mouse and human genes of the same subgroup is greater than between VH genes ofdifferent subgroups in the same species. The sequence also suggests that DNA repeats at the 5' and 3' regions flanking the VH gene can form a large stem-and-loop structure that may facilitate saltatory replication (15

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