The germline organizations of Ig and TCR genetic loci are fundamentally similar and are characterized by spatial segregation of multiple sequences that encode variable and constant domains of receptor proteins; distinct variable region sequences are joined to constant region sequences in different lymphocytes. We first describe the Ig loci and then the TCR loci.
Three separate loci encode, respectively, all the Ig heavy chains, the Ig k light chain, and the Ig X light chain. Each locus is on a different chromosome. The organization of human Ig genes is illustrated in Figure 8-5, and the relationship of gene segments after rearrangement to the domains of the Ig heavy and light chain proteins is shown in Figure 8-6A. Ig genes are organized in essentially the same way in all mammals, although their chromosomal locations and the number and sequence of different gene segments in each locus may vary.
At the 5' end of each of the Ig loci, there is a cluster of V gene segments, each V gene in the cluster being about 300 base pairs long. The numbers of V gene segments vary considerably among the different Ig loci and among different species. For example, there are about 35 V genes in the human k light chain locus, about 30 in the X locus, and about 100 functional V genes in the human heavy chain locus, whereas the mouse X light chain locus has only two V genes and the mouse heavy chain locus has more than 1000 V genes. The V gene segments for each locus are spaced over large stretches of DNA, up to 2000 kilobases long. Located 5' of each V segment is a leader exon that encodes the 20 to 30 N-terminal residues of the translated protein. These residues are moderately hydrophobic and make up the leader (or signal) peptide. Signal sequences are found in all newly synthesized secreted and transmembrane proteins and are involved in guiding nascent polypeptides being translated on membrane-bound ribosomes into the lumen of the endoplasmic reticulum. Here, the signal sequences are rapidly cleaved, and they are not present in the mature proteins. Upstream of each leader exon is a V gene promoter at which transcription can be initiated, but, as discussed later, this occurs most efficiently after rearrangement.
H chain locus (1250 kb; chromosome 14)
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