Antibody variable domain sequence diversity is generated by recombination of germline segments. The third complementarity-determining region of the heavy chain (CDR H3) is the region of highest sequence diversity and is formed by the joining of heavy chain VH, DH and JH germline segments combined with random nucleotide trimming and additions between these segments. We show that CDR H3 length distribution is biased in human antibody repertoires as a function of VH, VL and JH germline segment utilization. Most length biases are apparent in the naïve B cell compartment, with a significant bias towards shorter CDR H3 sequences observed in association with a subset of VH and VL germlines in the antigen experienced compartment. Similar biases were not observed in nonproductive heavy chain recombination products, indicating selection of the repertoire during B cell maturation as a major driver of the length biases. Some VH-associated CDR H3 length biases are dependent on utilization of specific JH germline segments in a manner not directly linked to JH segment length in the germline, but are rather associated with selection of differentially trimmed JH segments in the naïve compartment. In addition, DH segment and N-region random nucleotide insertion lengths within CDR H3 in the naïve compartment were also biased by specific VH/JH germline combinations, indicating a complex set of constraints between germline segments selected during repertoire maturation. Our findings reveal biases in the antibody diversity landscape shaped by VH, VL, and JH germline features with implications for mechanisms of naïve and immune repertoire selection.

These are subsets of datasets published by:

1. Goldstein, L. D. et al. Massively parallel single-cell B-cell receptor sequencing enables rapid discovery of diverse antigen-reactive antibodies. Commun Biol2, 304 (2019).

2. Busse, C. Dynamics of the human antibody repertoire after influenza vaccination. NCBI BioProject Database, https://www.ncbi.nlm.nih.gov/bioproject/PRJNA349143 (2016).

3. Laserson, U. et al. High-resolution antibody dynamics of vaccine-induced immune responses. Proc Natl Acad Sci U S A111, 4928-4933 (2014).

4. DeKosky, B. J. et al. In-depth determination and analysis of the human paired heavy- and light-chain antibody repertoire. Nat Med21, 86-91 (2015).

5. DeWitt, W. S. et al. A Public Database of Memory and Naive B-Cell Receptor Sequences. PLoS One 11, e0160853 (2016).

6. Briney, B., Inderbitzin, A., Joyce, C. & Burton, D. R. Commonality despite exceptional diversity in the baseline human antibody repertoire. Nature566, 393-397 (2019)

The datasets have been filtered for clonotypes, retaining a single sequence from each clonotype.