Clonotype specificity distinguishes epitope-tailored and permissive somatic hypermutation
- 1Icahn School of Medicine at Mount Sinai
Abstract
Identifying antibody features that reliably encode epitope specificity poses a major barrier towards modeling antigen-antibody interactions. Affinity maturation offers a unique opportunity to probe the molecular basis of antigen-antibody interactions by revealing how individual somatic hypermutations (SHM) refine antibody binding. Using SARS-CoV-2 spike-specific germinal center B-cell repertoires, we show that antibodies harboring multiple SHMs that are restricted to their respective clonotypes (clonotype-restricted SHMs) preferentially recognize cryptic epitopes. We structurally characterized three such antibodies: two recognized a cryptic epitope on the receptor-binding domain whereas a third bound an N-terminal domain epitope that is almost entirely occluded in prefusion spike. In contrast, SHMs shared across multiple clonotypes using the same V gene recur across antibodies targeting diverse antigens but generally fail to enhance affinity when introduced into diverse antibody backgrounds. Together, these findings define a spectrum of SHM behavior, distinguishing epitope-tailored mutations from broadly recurrent but largely permissive substitutions.
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BibTeX
@misc{rao2026clonotype,
title = {{Clonotype specificity distinguishes epitope-tailored and permissive somatic hypermutation}},
author = {V. N. Rao and B. Bonnettaz and A. Civljak and A. Abbad and F. Krammer and C. H. Coelho and G. Bajic},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.10.758199},
url = {https://www.biorxiv.org/content/10.64898/2026.10.10.758199v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Clonotype specificity distinguishes epitope-tailored and permissive somatic hypermutation
AU - V. N. Rao
AU - B. Bonnettaz
AU - A. Civljak
AU - A. Abbad
AU - F. Krammer
AU - C. H. Coelho
AU - G. Bajic
PY - 2026
DA - 2026/10/10
PB - bioRxiv
DO - 10.64898/2026.10.10.758199
UR - https://www.biorxiv.org/content/10.64898/2026.10.10.758199v1
AB - Identifying antibody features that reliably encode epitope specificity poses a major barrier towards modeling antigen-antibody interactions. Affinity maturation offers a unique opportunity to probe the molecular basis of antigen-antibody interactions by revealing how individual somatic hypermutations (SHM) refine antibody binding. Using SARS-CoV-2 spike-specific germinal center B-cell repertoires, we show that antibodies harboring multiple SHMs that are restricted to their respective clonotypes (clonotype-restricted SHMs) preferentially recognize cryptic epitopes. We structurally characterized three such antibodies: two recognized a cryptic epitope on the receptor-binding domain whereas a third bound an N-terminal domain epitope that is almost entirely occluded in prefusion spike. In contrast, SHMs shared across multiple clonotypes using the same V gene recur across antibodies targeting diverse antigens but generally fail to enhance affinity when introduced into diverse antibody backgrounds. Together, these findings define a spectrum of SHM behavior, distinguishing epitope-tailored mutations from broadly recurrent but largely permissive substitutions.
ER -