Learning the heterogeneous hypermutation landscape of immunoglobulins from high-throughput repertoire data

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Spisak, Natanael | Walczak, Aleksandra | Mora, Thierry

Edité par CCSD ; Oxford University Press -

International audience. Somatic hypermutations of immunoglobulin (Ig) genes occurring during affinity maturation drive B-cell receptors' ability to evolve strong binding to their antigenic targets. The landscape of these mutations is highly heterogeneous, with certain regions of the Ig gene being preferentially targeted. However, a rigorous quantification of this bias has been difficult because of phylogenetic correlations between sequences and the interference of selective forces. Here, we present an approach that corrects for these issues, and use it to learn a model of hypermuta-tion preferences from a recently published large IgH repertoire dataset. The obtained model predicts mutation profiles accurately and in a reproducible way, including in the previously uncharacterized Comple-mentarity Determining Region 3, revealing that both the sequence context of the mutation and its absolute position along the gene are important. In addition, we show that hypermutations occurring concomittantly along B-cell lineages tend to co-localize, suggesting a possible mechanism for accelerating affinity matu-ration.

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