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Characterization of LILRB3 and LILRA6 allelic variants in the Japanese population

Journal of Human Genetics volume 66, pages 739–748 (2021)Cite this article

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Abstract

Leukocyte immunoglobulin (Ig)-like receptors (LILRs) are encoded by members of a human multigene family, comprising 11 protein-coding genes and two pseudogenes. Among the LILRs, LILRB3 and LILRA6 show the highest homology with each other, along with high allelic and copy number variations. Therefore, it has been difficult to discriminate between them, both genetically and functionally, precluding disease association studies of LILRB3 and LILRA6. In this study, we carefully performed variant screening of LILRB3 and LILRA6 by cDNA cloning from Japanese individuals and identified four allelic lineages showing significantly high non-synonymous-to-synonymous ratios in pairwise comparisons. Furthermore, the extracellular domains of the LILRB3*JP6 and LILRA6*JP1 alleles were identical at the DNA level, suggesting that gene conversion-like events diversified LILRB3 and LILRA6. To determine the four allelic lineages from genomic DNA, we established a lineage typing method that accurately estimated the four allelic lineages in addition to specific common alleles from genomic DNA. Analysis of LILRA6 copy number variation revealed one, two, and three copies of LILRA6 in the Japanese-in-Tokyo (JPT) population. Flow cytometric analysis showed that an anti-LILRB3 antibody did not recognize the second most common lineage in the Japanese population, indicating significant amino acid differences across the allelic lineages. Taken together, our findings indicate that our lineage typing is useful for classifying the lineage-specific functions of LILRB3 and LILRA6, serving as the basis for disease association studies.

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Data availability

Data generated in this study are available from corresponding author upon reasonable request. Nucleotide sequence data reported are available in the DDBJ/EMBL/GenBank databases under the accession numbers LC579435 (LILRB3*JP1); LC599496 (LILRB3*JP1s); LC579436 (LILRB3*JP2); LC579437 (LILRB3*JP3); LC579438 (LILRB3*JP4); LC579439 (LILRB3*JP5); LC579440 (LILRB3*JP6); LC579441 (LILRB3*JP7); LC579442 (LILRA6*JP1); LC579443 (LILRA6*JP2); LC579444 (LILRA6*JP3); LC579445 (LILRA6*JP4); LC579446 (LILRA6*JP5); LC599497 (LILRA6*JP6)

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Acknowledgements

The authors would like to thank Ms. Momoka Kitajima (Department of Immunology, Graduate School of Medical Sciences, Kanazawa University) for technical assistance. This work was partly supported by PRIME from Japan Agency for Medical Research and Development, AMED under grant number JP20gm6010021 (K Hirayasu), JP20km0405205 (KT), JSPS KAKENHI grant number JP19H03468 (K Hirayasu), the Naito Foundation (K Hirayasu), and Takeda Science Foundation (K Hirayasu).

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Author notes

  1. These authors contributed equally: Kouyuki Hirayasu, Jinwen Sun

Authors and Affiliations

  1. Advanced Preventive Medical Sciences Research Center, Kanazawa University, Ishikawa, Japan

    Kouyuki Hirayasu, Yuko Hashikawa, Kazuyoshi Hosomichi, Atsushi Tajima & Rikinari Hanayama

  2. Department of Immunology, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan

    Kouyuki Hirayasu, Jinwen Sun, Gen Hasegawa & Rikinari Hanayama

  3. Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Ishikawa, Japan

    Kazuyoshi Hosomichi & Atsushi Tajima

  4. Genome Medical Science Project, National Center for Global Health and Medicine, Tokyo, Japan

    Katsushi Tokunaga

  5. Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan

    Jun Ohashi

  6. WPI Nano Life Science Institute (NanoLSI), Kanazawa University, Kakuma, Kanazawa, Ishikawa, Japan

    Rikinari Hanayama

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  1. Kouyuki Hirayasu
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Contributions

K Hirayasu designed and performed most of the experiments and wrote the manuscript. JS performed most of the experiments and analyzed and discussed the data. GH and YH assisted with the experiments. K Hosomichi assisted with data analyses. AT and KT provided suggestions for the study. JO assisted with data analyses and discussed the data. RH supervised the study. All authors read and approved the final manuscript.

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Correspondence to Kouyuki Hirayasu.

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This study was reviewed and approved by the research ethics committee of Kanazawa University.

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Hirayasu, K., Sun, J., Hasegawa, G. et al. Characterization of LILRB3 and LILRA6 allelic variants in the Japanese population. J Hum Genet 66, 739–748 (2021). https://doi.org/10.1038/s10038-021-00906-0

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