Junctional Flexibility Adds Diversity

The enormous diversity generated by means of V, D, and J combinations is further augmented by a phenomenon called junctional flexibility. As described above, recombination involves both the joining of recombination signal sequences to form a signal joint and the joining of coding sequences to form a coding joint (see Figure 5-7). Although the signal sequences are always joined precisely, joining of the coding sequences is often imprecise. In one study, for example, joining of the Vk21 and JK1 coding sequences was analyzed in several pre-B cell lines. Sequence analysis of the signal and coding joints revealed the contrast in junctional precision (Figure 5-12).

As illustrated previously, junctional flexibility leads to many nonproductive rearrangements, but it also generates productive combinations that encode alternative amino acids at each coding joint (see Figure 5-9), thereby increasing antibody diversity. The amino acid sequence variation gener-

Combinatorial antibody diversity in humans and mice

LIGHT CHAINS

Multiple germ-line segments

Heavy chain

ESTIMATED NUMBER OF SEGMENTS IN HUMANS*

Combinatorial V-D-J and V-J joining (possible number of combinations)

Possible combinatorial associations of heavy and light chains'"

51 27 6

ESTIMATED NUMBER OF SEGMENTS IN MICE*

Combinatorial V-D-J and V-J joining (possible number of combinations)

Possible combinatorial associations of heavy and light chains'

134 13 4

6968

2X3=6

*These numbers have been determined from studies of single subjects; slight differences may be seen among different individuals. Also, in the human case, only the functional gene segments have been listed. The genome contains additional segments that are incapable of rearrangement or contain stop codons or both. In the mouse case, the figures contained in the table are only best estimates, because the locus has not been completely sequenced.

'Because of the diversity contributed by junctional flexibility, P-region nucleotide addition, N-region nucleotide addition, and somatic mutation, the actual potential exceeds these estimates by several orders of magnitude.

vk21

Pre-B cell lines

Coding joints (vk21jk1)

Signal joints (RSS/RSS)

5'-CACTGTG

5'-CACTGTG

Cell line #2 5 '-GGATC TGGACGTT-3'

Cell line #3 5'-GGATCCTC GTGGACGTT-3' 5'-CACTGTG

Cell line #4 5'-GGATCCT TGGACGTT-3'

5'-CACTGTG

cacagtG-3'

CACAGTG-3'

cacagtG-3'

cacagtG-3'

FIGURE 5-12

Experimental evidence for junctional flexibility in im-munoglobulin-gene rearrangement. The nucleotide sequences flanking the coding joints between VK21 and JK1 and the corresponding signal joint sequences were determined in four pre-B cell lines. The sequence constancy in the signal joints contrasts with the sequence variability in the coding joints. Pink and yellow shading indicate nucleotides derived from VK21 and JK1, respectively, and purple and orange shading indicate nucleotides from the two RSSs.

ated by junctional flexibility in the coding joints has been shown to fall within the third hypervariable region (CDR3) in immunoglobulin heavy-chain and light-chain DNA (Table 5-3). Since CDR3 often makes a major contribution to antigen binding by the antibody molecule, amino acid changes generated by junctional flexibility are important in the generation of antibody diversity.

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Responses

  • Alvin
    What is junctional flexibility?
    8 years ago
  • Maciej
    Does jucntional flexibility happen in the cdr?
    5 months ago
  • asmara
    Does junctional flexibility only happen on the heavy chain?
    5 months ago

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