10 20 30 40 50 60 70 B0 90 Amino acid position

Figure 3 The patterns of germline diversity and somatic hypermutation. For each position, percentage somatic hypermutation (top of each panel, lighter tint) and germline variability (bottom of each panel, darker tint) are shown for (A) the human VH domain and (B) the human VK domain (corresponding plots for the domain are not shown here but can be found in Ignatovich et al (1997)). (Reproduced with permission from Tomlinson et al (1996).)

domains was then calculated (Figure 3). The CDRH3 and the end of the CDRL3 were not included in this analysis, as somatic hypermutation could not be distinguished from junctional diversity in this region. To compare the diversity introduced by somatic hypermutation with that present in the same repertoire of germline sequences, each of the rearranged genes was substituted with its corresponding germline VH, VK and Vx segment. Germline diversity at each position was then calculated using the Kabat variability index (Figure 3).

Germline diversity is found mostly in CDRH2, at residue 50 in the CDRL2 and at residues 91, 92 and 94 in the CDRL3. In contrast, somatic hypermutation is most prevalent in the CDRH1 and CDRL1 regions. In order to illustrate these patterns of germline diversity and somatic hypermutation, a representative antibody structure was used to provide an 'antigen's eye' view of the binding site. Before somatic hypermutation, germline diversity is concentrated at the centre of the antigen binding site. In contrast, somatic hypermutation spreads diversity to regions at the periphery of the binding site that are highly conserved in the primary repertoire. As a result, the final pattern of diversity (similar to that first represented by Kabat) is evenly distributed across the antigen binding site (see color plate 7).

The complementarity between germline diversity and somatic hypermutation seems to have evolved as an efficient strategy for producing high-affinity antibodies, given the limited number of B cells available for selection. Thus, antibodies are first selected from the primary repertoire based solely on the diversity at the center of the binding site. Somatic hypermutation is then left to optimize residues at the periphery without disrupting favorable interactions established during the primary response. The availability of a mechanism for somatic hypermutation has clearly led to the conservation of some sites in the germline V gene segments (for alteration by somatic hypermutation) and to the diversification of others. In this way, somatic hypermutation has left an evolutionary imprint on the repertoire of human germline V gene segments.

See also: Affinity maturation; Antibodies, specificity; Antigen-binding site; Immunoglobulin, evolution of; Immunoglobulin gene superfamily; Immunoglobulin structure; Antibody-antigen complexes, three-dimensional structures.

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