Summary
A diverse immune repertoire is considered a hallmark of good health. However, other things being equal, current methods for measuring repertoire diversity do not distinguish between a repertoire that is composed of similar sequences, clonotypes, or clones and a repertoire that is composed of different ones, even though the latter is intuitively more diverse. Here we describe a framework for incorporating similarity into diversity measures, and illustrate using … define diversity with binding similarity as functional diversity, and measure functional diversity on 391 large-scale antibody and T-cell receptor (TCR) repertoires. We find that while repertoires often contain millions of unique sequences, functional diversity reveals a landscape defined by at most a few thousand unrelated CDR3 binding targets. Naïve/IgM repertoires have more unique sequences than memory/IgG, but memory/IgG repertoires are more functionally diverse. Functional diversity is sensitive to vaccination, infection, and aging, and unlike raw diversity is robust to sampling error. Finally, according to functional diversity, repertoires from different people overlap significantly, suggesting a definable ceiling for the functional diversity of humanity. Similarity redefines diversity in complex systems.