NAddition Adds Considerable Diversity by Addition of Nucleotides

Variable-region coding joints in rearranged heavy-chain genes have been shown to contain short amino acid sequences that are not encoded by the germ-line V, D, or J gene segments. These amino acids are encoded by nucleotides added during the D-J and V to D-J joining process by a terminal deoxynucleotidyl transferase (TdT) catalyzed reaction

Sources of sequence variation in complementarity-determining regions of immunoglobulin heavy- and light-chain genes

Sources of sequence variation in complementarity-determining regions of immunoglobulin heavy- and light-chain genes

Source of variation

Source of variation

CDR1

CDR2

CDR3

V segment V segment VL-JL junction;

Vh-Dh-Jh junctions

Sequence encoded by:

Junctional flexibility

P-nucleotide addition

N-nucleotide addition*

Somatic hypermutation

*N-nucleotide addition occurs only in heavy-chain DNA.

(Figure 5-13b). Evidence that TdT is responsible for the addition of these N-nucleotides has come from transfection studies in fibroblasts. When fibroblasts were transfected with the RAG-1 and RAG-2 genes, V-D-J rearrangement occurred but no N-nucleotides were present in the coding joints. However, when the fibroblasts were also transfected with the gene encoding TdT, then V-D-J rearrangement was accompanied by addition of N-nucleotides at the coding joints.

Up to 15 N-nucleotides can be added to both the DH-JH and VH-DHJH joints. Thus, a complete heavy-chain variable region is encoded by a VHNDHNJH unit. The additional heavy-chain diversity generated by N-region nucleotide addition is quite large because N regions appear to consist of wholly random sequences. Since this diversity occurs at V-D-J coding joints, it is localized in CDR3 of the heavy-chain genes.

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