Lack of evidence for a substantial rate of templated mutagenesis in B cell diversification

TL;DR

This study critically re-evaluates the proposed high rate of templated mutagenesis in B cell diversification, finding that if it occurs, it is at a low rate, and that previous claims may be due to model misspecification.

Contribution

The paper challenges prior claims of high templated mutagenesis rates by analyzing false positive rates and null model specifications, suggesting the process is likely rare.

Findings

False positive rates are similar or higher than original estimates.

Evidence suggests templated mutagenesis, if present, is at a low rate.

Original significant results may result from null model misspecification.

Abstract

B cell receptor 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 immunoglobulin diversification, in mice and humans. In this proposed process, mutations in the immunoglobulin locus are introduced by copying short segments from other immunoglobulin genes. If true, this would overturn decades of research on B cell diversification, and would require a complete re-write 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's false positive rates. We find false positive rates of templated mutagenesis in murine and human immunoglobulin 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.