Distinct frequency patterns of LILRB3 and LILRA6 allelic variants in Europeans

The leukocyte immunoglobulin-like receptor (LILR)B3 and LILRA6 genes encode homologous myeloid inhibitory and activating orphan receptors, respectively. Both genes exhibit a strikingly high level of polymorphism at the amino acid level and LILRA6 (but not LILRB3) displays copy number variation (CNV). Although multiple alleles have been reported for both genes, limited data is available on frequencies of these alleles among humans. We have sequenced LILRB3/A6 exons encoding signal peptides and ectodomains in 91 healthy blood donors of European descent who carry one or two copies of LILRA6 per diploid genome. Analysis of haplotypes among individuals with two LILRA6 copies, representing the majority in this cohort (N = 86), shows that common LILRB3 and LILRA6 alleles encode some distinct amino acid sequences in homologous regions of the receptors, which could potentially impact their respective functions differentially. Comparison of sequences in individuals with one vs. two copies of LILRA6 supports non-allelic homologous recombination between LILRB3 and LILRA6 as a mechanism for generating LILRA6 CNV and LILRB3 diversity. These data characterize LILRB3/LILRA6 genetic variation in more detail than previously described and underscore the need to determine their ligands.

Automated summary

The genes LILRB3 and LILRA6 encode homologous receptors with inhibitory and activating functions, respectively. These genes exhibit high levels of polymorphism at the amino acid level, and LILRA6 shows variation in copy number. By analyzing the genetic variation in 91 individuals, it was found that common alleles of LILRB3 and LILRA6 encode different amino acid sequences in homologous regions, potentially affecting their functions differently. Furthermore, the comparison of sequences in individuals with different copy numbers of LILRA6 suggests a mechanism of non-allelic homologous recombination between LILRB3 and LILRA6. These findings provide a detailed characterization of LILRB3/LILRA6 genetic variation and highlight the need for determining their ligands.