The number of germline genes specifying the variable sequences of the Vkappa21 group of light chains was determined by saturation hybridisation analysis to be four to six. This gene multiplicity is considerably less than the total variability in the group, indicating that kappa-chain diversity is generated by somatic mutations in both framework and complementarity-determining (hypervariable) regions.

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What controls the transcription of immunoglobulin genes?

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A biological consequence of variation in the site of D-JH gene rearrangement.

One mechanism which generates diversity in immunoglobulin variable (V) regions is flexibility in the site of recombination among the constituent genetic elements. Within a specific antibody family (that is, a particular VH-VL combination), variability in V-D-J rearrangement not only leads to sequence diversity at the boundary of the juxtaposed genes, but also enables the total length of the third complementarity-determining region (CDR-3) of the heavy chain to be conserved. We demonstrate here that the junctional diversity inherent in rearranged immunoglobulin genes can have consequences for the biology of the immune system. Sequence analysis of the expressed immunoglobulin genes of idiotypically variant as opposed to conventional B lymphocytes of a dominant antibody family showed that the variant B cells undergo a novel D-JH joining event such that an extra amino acid is inserted into the heavy chain CDR-3. The unique D-region conformation possessed by the variant B cells accounts for previous observations which showed that variant and conventional B cells could be differentially regulated in vivo by an autologous set of idiotope-specific B lymphocytes. Our findings indicate that D-region structure can determine the expression of regulatory idiotopes and suggest that the conservation of heavy-chain CDR-3 length within an antibody family may reflect regulatory as well as functional constraints.

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C mu-containing transcripts initiate heterogeneously within the IgH enhancer region and contain a novel 5'-nontranslatable exon.

Transcriptional competence of the immunoglobulin heavy-chain locus (IgH) is established at an early stage of lymphoid cell development, leading to the appearance of RNA components, previously called C mu RNA1 or sterile-mu RNA2, which contain constant-region sequences but lack variable-region sequences. These components are of two types: those which initiate in the D region of alleles that have undergone DJH (diversity-joining region) rearrangement (D mu transcripts) and those which initiate within the JH-C mu intron (hereafter termed I mu transcripts). In pre-B and early B cells, D mu and I mu transcripts are nearly as abundant as the messenger RNA encoding mu heavy chain. The D mu transcripts are spliced into RNAs containing D, JH and C mu sequences, and in some, but not all, cases these RNAs are translated into D mu proteins. To establish whether the I mu transcripts have any translational potential and to elucidate the structure of their promoter region, we have determined their transcription initiation sites and their mode of splicing. As reported here, by using sequence analysis of cloned I mu complementary DNAs, primer extension and S1 nuclease mapping, we have found that these transcripts have remarkable 5' heterogeneity: there are more than five distinct start sites spanning a region of 44 nucleotides that is located downstream of an octanucleotide found in all variable-region promoters. Such imprecise initiation may result from the lack of a well-defined TATAA motif and the unusual proximity of the octanucleotide to the enhancer region. Approximately 700 nucleotides downstream from these initiation sites, a cryptic splice site is used to create a nontranslatable exon ('nontron') which is joined to the C mu 1 domain. The properties of the nontron may be important for the mechanism of allelic exclusion.

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