Evolution of somatic hypermutation and gene conversion in adaptive immunity

Abstract

Summary: Examples of somatic hypermutation of antigen receptor genes can be seen in most lineages of vertebrates, including the cartilaginous fish. Analysis of the phylogenetic data reveals that two distinctive features of the mechanism are shared by most species studied: the mutation hot spot sequence AGY, and a preponderance of point mutations. These data suggest that some of the components of the machinery are shared between ectotherms and mammals. However, unique characters in particular species may have occurred by independent recruitment of novel factors onto the mechanisni. A spotty phylogenetic distribution of gene conversion has also been revealed and can be explained if the two mechanisms share some characteristics. Both mutation and conversion require transcription-related sequences and/or factors. We theorized that targeting to V genes can be attained by a paused replication fork that has collided with a transcription complex stalled by a defective Ig transcription activator; the paused replication fork results in recruitment of an error-prone translesion synthesis DNA polymerase (somatic hypermutation) or of DNA repair mechanisms with homologous recombination (gene conversion). In addition, the pathway recruited in different species may be directed by the degree of homology among V genes.