GSSP plots

Somatic
hypermutation (SHM) plays a critical role in the maturation of
antibodies, optimizing recognition initiated by recombination of
V(D)J genes. Previous studies have shown that the propensity to
mutate is modulated by the context of surrounding nucleotides and
that SHM machinery generates biased substitutions. To investigate the
mutation frequency and substitution bias of SHMs, context-dependent
substitution models have been developed at the nucleotide level.
However, no context-dependent model has been developed to
systematically characterize the intrinsic mutation frequency and
substitution bias of SHMs at the amino acid level. In this study, we
analyzed functional human antibody repertoires and developed mGSSP
(method for Gene-Specific Substitution Profile), a method to
construct amino acid substitution profiles from next-generation
sequencing-acquired B cell transcripts. These
gene-specific substitution profiles (GSSP) are unique to each V gene
and highly consistent between donors. By implicitly incorporating context-dependence, GSSPs
provide an alternative means for accurate modeling of the SHM
process, and provide a means for characterizing features of SHM
mutational space, predicting mutational propensities of SHMs, and for
better understanding maturation pathways of antibody lineages in a
gene-specific context. To date, extensive efforts have been invested
to re-elicit naturally occurring broadly neutralizing antibodies
against HIV-1 and other pathogens in humans and animal models.
Incorporating GSSPs into the modeling of the SHM process may help
predict the likelihood of re-eliciting key SHM patterns of interest.
These figures show GSSPs for VH, VK, and VL genes with at least 300
lineages present in the pooled sequencing data from three normal donors.