The Nucleotide Targets of Somatic Mutation and the Role of Selection in Immunoglobulin Heavy Chains of a Teleost Fish

Abstract

Sequence analysis of H chain cDNA derived from the spleen of an individual catfish has shown that somatic mutation occurs within both the VH- and JH-encoded regions. Somatic mutation preferentially targets G and C nucleotides with approximately balanced frequencies, resulting in the predominant accumulation of G-to-A and C-to-T substitutions that parallel the activation-induced cytidine deaminase nucleotide exchanges known in mammals. The overall mutation rate of A nucleotides is not significantly different from that expected by sequence-insensitive mutations, and a significant bias exists against mutations occurring in T. Targeting of mutations is dependent upon the sequence of neighboring nucleotides, allowing statistically significant hotspot motifs to be identified. Dinucleotide, trinucleotide, and RGYW analyses showed that mutational targets in catfish are restricted when compared with the spectrum of targets known in mammals. The preferential targets for G and C mutation are the central GC positions in both AGCT and AGCA. The WA motif, recognized as a mammalian hotspot for A mutations, was not a significant target for catfish mutations. The only significant target for A mutations was the terminal position in AGCA. Lastly, comparisons of mutations located in framework region and CDR codons coupled with multinomial distribution studies found no substantial evidence in either independent or clonally related VDJ rearrangements to indicate that somatic mutation coevolved with mechanisms that select B cells based upon nonsynonymous mutations within CDR-encoded regions. These results suggest that the principal role of somatic mutation early in phylogeny was to diversify the repertoire by targeting hotspot motifs preferentially located within CDR-encoded regions.

Evolutionary dynamics of the immunoglobulin heavy chain variable region genes in vertebrates

“…After the activation of B cells, somatic hypermutation (SHM) introduces additional diversity and can improve the antigen-binding affinity of the expressed antibodies (Cannon et al 2004). The enzyme activation-induced cytidine deaminase (AID) is known to be required for inducing SHM (Cannon et al 2004;Yang et al 2006). The role of AID in bonyfishes is still unclear.…”

“…The role of AID in bonyfishes is still unclear. Although a recent study indicates the presence of SHM in fishes, the spectrum of mutational targets is restricted in comparisons to mammals (Yang et al 2006). Hence, it is possible that in fishes, a high degree of intraspecies variation of IGHV sequences may compensate for the apparently poor somatic hypermutation in generation of antibody diversity.…”

Differential compartmentalization of memory B cells versus plasma cells in salmonid fish

“…Intriguingly, characteristics of teleost memory B cells (MBCs) [9] parallel those associated with a class of mammalian MBCs. Recent evidence reveals that human MBCs can include unswitched, mutated IgM + cells [23]; nonmutated, CD27 + IgM + cells [24], those induced by T-independent (TI) antigens [25,26], preimmune diversified repertoires [27] (as has recently been posed for the catfish [19]), or arise independently of GCs [27,28]. Together, these previous studies prompt a renewed focus on the critical elements of μ specific memory, both in teleosts and mammals.…”

“…Primary immunization can, thus, lead to increased immunogen sensitivity [1], enhanced in vivo [2][3][4][5][6] and in vitro [6][7][8] antibody responsiveness, expansion of antigen-sensitive precursor pools [9] and, most importantly, anamestic responses to pathogens [4,5,10,11] and immunoprophylaxis [4,[12][13][14]. Anamestic features absent from teleost responses include isotype switching [15] (although they possess multiple isotypes [16]), relatively modest somatic mutaCorrespondence: Dr. Stephen L. Kaattari e-mail: kaattari@vims.edu tion [17][18][19] and affinity maturation [20][21][22] as compared with the IgG responses of mammals. Intriguingly, characteristics of teleost memory B cells (MBCs) [9] parallel those associated with a class of mammalian MBCs.…”

Arche de Noé immunologique

“…Le système lymphoïde secondaire est plus sommaire que celui des mammifères. Les poissons possèdent bien un système élaboré de canaux lymphatiques drainant les tissus superficiels [3], mais ils n'ont pas de [11] ; ces mutations joueraient plutôt un rôle de diversification du répertoire initial [12]. Une autre propriété remarquable des lymphocytes B des poissons est leur capacité de phagocyter et dégrader des bactéries [13].…”