Structure and expression of the human immunoglobulin lambda genes.

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Abstract
We determined the DNA sequence of two large regions of chromosome 22:33.7 kb containing the C.lambda. complex; and 5.2 kb 5'' of the functionally rearranged .lambda. gene from the human myeloma, U266. Analysis of these sequences reveals the complete structure of the human C.lambda. complex and a previously undescribed seventh C.lambda. region that may encode the Ke+Oz- .lambda. protein. The seven constant regions are organized in a tandem array, and each is preceded by a single J.lambda. region. .lambda.1, .lambda.2, .lambda.3, and .lambda.7 are apparently active genes, while .lambda.4, .lambda.5, and .lambda.6 are pseudogenes. There are no other J.lambda. or C.lambda. regions within a 60-kb region surrounding the C.lambda. complex; however, there are at least four other .lambda.-like genes and .lambda. pseudogenes in the human genome. The .lambda. genes appear to have evolved via a series of gene duplication events resulting from unequal crossing over or gene conversion between the highly conserved C.lambda. regions on mispaired chromosomes. The lack of Alu sequences in this large segment of DNA suggests that the C.lambda. complex resulted from a recent amplification of a smaller Alu-free segment of DNA. Illegitimate recombination between repeated sequences containing .lambda.2 and .lambda.3 may be responsible for variable amplification of the .lambda. genes. We also found a 1,377-bp open reading frame (ORF) located on the opposite strand in the region containing .lambda.7. While this ORF is flanked by potential RNA splicing signals, we have no evidence that it is part of a functional gene. We also discovered a V.lambda. pseudogene, called .psi.V.lambda.1, 3 kb upstream of the U266.lambda. gene. Using primer extension analysis to map the transcription start in the human .lambda. gene, we have identified its initiation point 41 upstream of the initiation codon. Analysis of the .lambda. promoter reveals that it contains a TATAA box at position -29 relative to the transcription initiation site and an octamer sequence at -67. Computer anlaysis of 40 kb of DNA sequences surrounding the human .lambda. locus has revealed no consequences resembling the .kappa. or IgH transcriptional enhancers, nor have in vitro analyses for function revealed enhancer activity. A comparison of these results with those obtained in separate studies with transgenic mice point to a complex, developmentally linked mechanism of transcriptional activation.