Evolutionary Perspective

As the biologic instructions of life, the maintenance of DNA is a critical component of an organism’s basic functions. That being so, all life has devised strategies for preserving DNA fidelity. In fact, many of these DNA repair systems are conserved across all domains of life, highlighting the importance of the process to the last common cellular ancestor and all descended life since.

Gene conversion (templated mutagenesis) is one of these evolutionarily-ancient mechanisms of DNA repair. From use in fungi and yeast for maintenance of genetic stability, to the generation of somatic diversity in the adaptive immune system of vertebrates, gene conversion plays an integral role in shaping and maintaining genetic landscapes. For Agnathans (jawless vertebrates) – who possess the oldest adaptive immune system – gene conversion conducts the genetic assembly of antibody analogues, known as VLRs. Descendants of Gnathostomes (jawed vertebrates), which share a common ancestor with Agnathans ~500 million years ago, include the classes Aves (birds) and Mammalia (mammals). These two classes diverged ~310 million years ago from each other, yet they both retain widespread use of conversion during somatic diversification of antibodies.

Despite the evolutionarily-conserved use of gene conversion, it has been reported that this mechanism does not contribute significantly to antibody maturation in terminal members of Mammalia, Mus musculus and Homo sapiens.

Historical Context

Since Paul Ehrlich’s description of the “magic bullet” in 1908, the breadth and specificity of antibodies have been a focal point of understanding humoral immunity. Although many advances were made in the years since he first described this concept, it was not until the early 1980s when studies by Gearhart, Selsing, and Bothwell began to decipher the molecular basis for this - somatic mutations in antibody encoding sequences.

Though mutations were known to occur, the mechanism by which they did remained unknown until the late 1980s when studies by Reynaud identified what she termed “somatic hyperconversion” in chicken B cells. These cells had a single functional antibody sequence at the antibody locus along with a number of upstream pseudogenes. The relative simplicity of this locus made it possible to easily identify these hyperconversion events (otherwise known as gene conversion).

Follow up studies in mice and humans did not identify such a mechanism, although sporadic reports of gene conversion did occur. Thus, the field sought another explanation for the diversity of somatic mutants in human and murine B cells. It was 2000, that Muramatsu discovered activation-induced cytidine deaminase (AID) which introduced point mutations at the antibody locus. This gene was later also described to be critical to gene conversion. However, since human and murine B cells did not appear to carry out gene conversion, the field moved towards an independent mechanism that relied on AID activity and subsequent processing by base-excision repair, mismatch repair, and error prone polymerases.