IgGene Rearrangements May Be Productive or Nonproductive

One of the striking features of gene-segment recombination is the diversity of the coding joints that are formed between any two gene segments. Although the double-strand DNA breaks that initiate V-(D)-J rearrangements are introduced precisely at the junctions of signal sequences and coding sequences, the subsequent joining of the coding sequences is imprecise. Junctional diversity at the V-J and V-D-J coding joints is generated by a number of mechanisms: variation in cutting of the hairpin to generate P-nucleotides, variation in trimming of the coding sequences, variation in N-nucleotide addition, and flexibility in joining the coding sequences. The introduction of randomness in the joining process helps generate antibody diversity by contributing to the hypervariabil-ity of the antigen-binding site. (This phenomenon is covered in more detail below in the section on generation of antibody diversity.)

Another consequence of imprecise joining is that gene segments may be joined out of phase, so that the triplet reading frame for translation is not preserved. In such a nonproductive rearrangement, the resulting VJ or VDJ unit is likely to contain numerous stop codons, which interrupt translation (Figure 5-9). When gene segments are joined in phase, the reading frame is maintained. In such a productive rearrangement, the resulting VJ or VDJ unit can be translated in its entirety, yielding a complete antibody.

If one allele rearranges nonproductively, a B cell may still be able to rearrange the other allele productively. If an inphase rearranged heavy-chain and light-chain gene are not produced, the B cell dies by apoptosis. It is estimated that only one in three attempts at VL-JL joining, and one in three subsequent attempts at VH-DHJH joining, are productive. As a result, less than 1/9 (11%) of the early-stage pre-B cells in the bone marrow progress to maturity and leave the bone marrow as mature immunocompetent B cells.

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Essentials of Human Physiology

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