Recurrent antibody repertoire features associated with six selected human IGHV genes: V(D)J usage, heavy-light pairing, and CDRH3 properties.

INTRODUCTION

Several human IGHV genes recur in infection, autoreactivity, B-cell malignancy, and antibody-discovery studies, but their downstream V(D)J usage, observed heavy-light pairing, and CDRH3 properties have rarely been examined together in paired human repertoires.

METHODS

We assembled 3,003,127 paired heavy- and light-chain records from public Observed Antibody Space (OAS) source files. After quality control, gene-level standardization, and exact-clonotype collapsing, the primary six-gene analysis included 712,143 exact clonotypes assigned to IGHV1-2, IGHV1-69, IGHV3-21, IGHV3-23, IGHV3-30, or IGHV4-34.

RESULTS

Marginal V-D effects were generally modest, whereas recurrent V-conditioned D-J modules and IGHV-associated VH-VL enrichment or depletion were repeatedly observed across OAS study groups in productive expressed repertoires. Several VH-VL directions persisted across studies and metadata-defined immune contexts, although two pairs were context-sensitive. External comparison with PairedAbNGS supported 8 of 10 evaluable key VH-VL directions and the broad IGHV-associated CDRH3 profiles. IGHV4-34 showed a study-robust, cross-resource positive shift in CDRH3 side-chain charge score.

DISCUSSION: Together, these analyses provide a study-aware reference for V-conditioned D-J usage, VH-VL associations, and CDRH3 properties across six selected IGHV backgrounds, while defining the limits imposed by immune-context heterogeneity and productive-repertoire sampling.