Lack of Evidence for a Substantial Rate of Templated Mutagenesis in B Cell Diversification

BCR sequences diversify through mutations introduced by purpose-built cellular machinery. A recent paper has concluded that a "templated mutagenesis" process is a major contributor to somatic hypermutation and therefore Ig diversification in mice and humans. In this proposed process, mutations in the Ig locus are introduced by copying short segments from other Ig genes. If true, this would overturn decades of research on B cell diversification and would require a complete rewrite of computational methods to analyze B cell data for these species. In this paper, we re-evaluate the templated mutagenesis hypothesis. By applying the original inferential method using potential donor templates absent from B cell genomes, we obtain estimates of the methods' false positive rates. We find false positive rates of templated mutagenesis in murine and human Ig loci that are similar to or even higher than the original rate inferences, and by considering the bases used in substitution, we find evidence that if templated mutagenesis occurs, it is at a low rate. We also show that the statistically significant results in the original paper can easily result from a slight misspecification of the null model.