Genetically and Functionally Distinct Immunoglobulin Heavy Chain Locus Duplication in Bats

The genetic locus encoding immunoglobulin heavy chains (IgH) is critical for vertebrate humoral immune responses and diverse antibody repertoires. Immunoglobulin and T cell receptor loci of most bat species have not been annotated, despite the recurrent role of bats as viral reservoirs and sources of zoonotic pathogens. We investigated the genetic structure and function of IgH loci across the largest bat family, Vespertilionidae, focusing on big brown bats (Eptesicus fuscus). We discovered that E. fuscus and ten other species within Vespertilionidae have two complete, functional, and distinct immunoglobulin heavy chain loci on separate chromosomes. This locus organization is previously unknown in mammals, but is reminiscent of more limited duplicated loci in teleost fish. Single cell transcriptomic data validate functional rearrangement and expression of immunoglobulin heavy chains of both loci in the expressed repertoire of Eptesicus fuscus, with maintenance of allelic exclusion, bias of usage toward the smaller and more compact IgH locus, and evidence of differential selection of antigen-experienced B cells and plasma cells varying by IgH locus use. This represents a unique mechanism for mammalian humoral immunity and may contribute to bat resistance to viral pathogenesis.