Learning the statistics and landscape of somatic mutation-induced insertions and deletions in antibodies

Affinity maturation is crucial for improving the binding affinity of antibodies to antigens. This process is mainly driven by point substitutions caused by somatic hypermutations of the immunoglobulin gene. It also includes deletions and insertions of genomic material known as indels. While the landscape of point substitutions has been extensively studied, a detailed statistical description of indels is still lacking. Here we present a probabilistic inference tool to learn the statistics of indels from repertoire sequencing data, which overcomes the pitfalls and biases of standard annotation methods. The model includes antibody-specific maturation ages to account for variable mutational loads in the repertoire. After validation on synthetic data, we applied our tool to a large dataset of human immunoglobulin heavy chains. The inferred model allows us to identify universal statistical features of indels in heavy chains. We report distinct insertion and deletion hotspots, and show that the distribution of lengths of indels follows a geometric distribution, which puts constraints on future mechanistic models of the hypermutation process. Author summary Affinity maturation of B cell receptors is an important mechanism by which our body designs neutralizing antibodies to defend us against pathogens, including broadly neutralizing antibodies, which target a wide range of variants of the same pathogen. Such antibodies often contain key insertions and deletions to the germline gene, or "indels", which are caused by somatic hypermutations. However, the mechanism, frequency and role of these indels are still elusive. We designed a computational method based on a probabilistic framework to infer the characteristics of this mutational process from high-throughput antibody sequencing experiments. Applied to human data, our approach provides a comprehensive quantitative description of insertions and deletions, opening avenues for better understanding the process of affinity maturation and the design of vaccines for eliciting a broad antibody response.