Evolution and the molecular basis of somatic hypermutation of antigen receptor genes

Abstract

Somatic hypermutation of immunoglobulin genes occurs in many vertebrates including sharks, frogs, camels, humans and mice. Similarities among species reveal a common mechanism and these include the AGC/T sequence hot spot, preponderance of base substitutions, a bias towards transitions and strand bias. There are some di¡erences among species, however, that may unveil layers of the mechanism. These include a G:C bias in frog and shark IgM but not in nurse shark antigen receptor (NAR), a high frequency of doublets in NAR hypermutation, and the co-occurrence of somatic hypermutation with gene conversion in some species. Here we argue that some of the similarities and di¡erences among species are best explained by error-prone DNA synthesis by the translesion synthesis DNA polymerase zeta (Pol z) and, as suggested by others, induction of DNA synthesis by DNA breaks in antigen receptor variable genes. Finally, targeting of the variable genes is probably obtained via transcription-related elements, and it is the targeting phase of somatic hypermutation that is the most likely to reveal molecules unique to adaptive immunity.

Unique Features of Fish Immune Repertoires: Particularities of Adaptive Immunity Within the Largest Group of Vertebrates

“…Although fishes lack conventional class switch (Stavnezer and Amemiya 2004), fish AID has similar biochemical functions and deaminates cytosine, thus inducing point mutations; it even mediates class switch in mouse B cells (Barreto et al 2005). The mutational pattern observed in Ig sequences from catfish (Yang et al 2006), zebrafish (Marianes et al 2011), and also in nurse shark (Diaz et al 1999) reminds actually the one described in mammals, with a preference for transitions but no major bias for mutation of G:C or A:T pairs (Diaz et al 2001). …”

Structural and Functional Characterization of Complement C4 and C1s-Like Molecules in Teleost Fish: Insights into the Evolution of Classical and Alternative Pathways

“…Only the lectin and the alternative pathways have been demonstrated to be present in deuterostome invertebrates (5,7,18,42). The absence of a complete classical pathway in these animals is probably due to their lack of adaptive immunity (i.e., Ig molecules) (43,44). It is hypothesized that the appearance of molecules involved in the activation of the classical pathway coevolved coordinately with the appearance of Ig molecules in cartilaginous and teleost fish (19).…”

Decreased Frequency of Somatic Hypermutation and Impaired Affinity Maturation but Intact Germinal Center Formation in Mice Expressing Antisense RNA to DNA Polymerase ζ

“…The mutation frequency, the enhancement of mutability by secondary structure, and the transition bias implicate a role for error-prone polymerase activity in somatic hypermutation, as originally proposed by Brenner and Milstein (29). The high frequency of doublets in the shark new Ag receptor mutants implies extension from a mismatched base pair, and such data, together with the predominance of base substitutions, suggest that the error-prone activity may be dependent on DNA polymerase (Pol ) (18,30,31). Pol catalyzes the bypass of DNA lesions that normally stall replication forks (32).…”