The human genome contains approximately 20 thousand protein-coding genes1, but the size of the collection of antigen receptors of the adaptive immune system that is generated by the recombination of gene segments with non-templated junctional additions (on B cells) is unknown—although it is certainly orders of magnitude larger. It has not been established whether individuals possess unique (or private) repertoires or substantial components of shared (or public) repertoires. Here we sequence recombined and expressed B cell receptor genes in several individuals to determine the size of their B cell receptor repertoires, and the extent to which these are shared between individuals. Our experiments revealed that the circulating repertoire of each individual contained between 9 and 17 million B cell clonotypes. The three individuals that we studied shared many clonotypes, including between 1 and 6% of B cell heavy-chain clonotypes shared between two subjects (0.3% of clonotypes shared by all three) and 20 to 34% of λ or κ light chains shared between two subjects (16 or 22% of λ or κ light chains, respectively, were shared by all three). Some of the B cell clonotypes had thousands of clones, or somatic variants, within the clonotype lineage. Although some of these shared lineages might be driven by exposure to common antigens, previous exposure to foreign antigens was not the only force that shaped the shared repertoires, as we also identified shared clonotypes in umbilical cord blood samples and all adult repertoires. The unexpectedly high prevalence of shared clonotypes in B cell repertoires, and identification of the sequences of these shared clonotypes, should enable better understanding of the role of B cell immune repertoires in health and disease.
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Sequencing data for HIP and CORD datasets have been deposited in the NCBI Sequence Read Archive under project number PRJNA511481. FASTA files for Adaptive Biotechnologies datasets used for analyses are available from https://github.com/crowelab/PyIR. Any other relevant data are available from the corresponding author upon reasonable request.
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We thank M. Mayo and A. Pruijssers for regulatory and human subjects support; G. Sapparapu and O. Koues for technical help; Y. Umareddy for assistance with R; S. B. Day for assistance with artwork; scientists at the VANTAGE core of Vanderbilt University Medical Center (VUMC), Adaptive Biotechnologies, the Genomic Services Laboratory at the Hudson Alpha Institute for Biotechnology, and D. Zhang and team at Abhelix; New England BioLabs for early access to pre-release Abseq reagents; K. Trochez and J. Janssen of the Clinical Trials Center at VUMC and staff and physicians of the Vanderbilt University Medical Center leukapheresis clinic for assistance with large-scale human cell collections; and S. Mallal and M. Pilkinton (Vanderbilt), R. Scheuermann (JCVI), and W. Koff, T. Schenkelberg and the Advisory Board of the Human Vaccines Project for helpful discussions. This work was conducted in part using the resources of the Advanced Computing Center for Research and Education (ACCRE) at Vanderbilt University and the San Diego Supercomputer Center at the University of California, San Diego. We acknowledge the use of cord blood cells procured by the National Disease Research Interchange (NDRI) with support from NIH grant U42 OD11158. This work was supported by a grant from the Human Vaccines Project, and institutional funding from Vanderbilt University Medical Center.
Nature thanks R. Arnaout, F. Breden, A. McHardy and the other anonymous reviewer(s) for their contribution to the peer review of this work.