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Identification of novel polymorphisms and two distinct haplotype structures in dog leukocyte antigen class I genes: DLA-88, DLA-12 and DLA-64

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Abstract

The current information on the polymorphism variation and haplotype structure of the domestic dog leukocyte antigen (DLA) genes is limited in comparison to other experimental animals. In this paper, to better elucidate the degree and types of polymorphisms and genetic differences for DLA-88, DLA-12 and DLA-64, we genotyped four families of 38 beagles and another 404 unrelated dogs representing 49 breeds by RT-PCR based Sanger sequencing. We also sequenced and analyzed the genomic organization of the DLA-88 and DLA-12 gene segments to better define these two-gene DLA haplotypes more precisely. We identified 45 alleles for DLA-88, 15 for DLA-12 and six for DLA-64, of which 20, 14 and six, respectively, were newly described alleles. Therefore, this study shows that the DLA-12 and DLA-64 loci are far more polymorphic than previously reported. Phylogenetic analysis strongly supported that the DLA-88, DLA-12 and DLA-64 alleles were independently generated after the original divergence of the DLA-79 alleles. Two distinct DLA-88 and DLA-12 haplotype structures, tentatively named DLA-88–DLA-12 and DLA-88–DLA-88L, were identified, and the novel haplotype DLA-88–DLA-88L contributed to 32.7% of the unrelated dogs. Quantitative real-time PCR analysis showed that the gene expression levels of DLA-88L and DLA-88 were similar, and that the gene expression level of DLA-12 was significantly lower. In addition, haplotype frequency estimations using frequently occurring alleles revealed 45 different DLA-class I haplotypes (88-88L/12-64) overall, and 22 different DLA-class I haplotypes in homozygous dogs for 18 breeds and mongrels.

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Acknowledgments

We thank Toshihiro Watari in Animal Medical Center (ANMEC) at Nihon University, Shinichi Namba in Marble Veterinary Medical center (Fujisawa, Japan) and Oriental Yeast Co. Ltd. (Tokyo, Japan) for providing the dog blood samples. We also thank Atsuko Shigenari and Sayaka Ito in Department of Molecular Life Science in Tokai University School of Medicine for technical assistance. This work was supported by Nihon University President’s Grant for Multidisciplinary Studies.

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Authors and Affiliations

  1. Department of Bio Resource Science, Nihon University School of Veterinary Medicine, 1866 Kameino, Fujisawa, Kanagawa, 252-0880, Japan

    Jiro Miyamae, Fumihiko Katakura, Sae Uno, Mizuki Tanaka, Masaharu Okano & Tadaaki Moritomo

  2. Department of Molecular Life Science, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1143, Japan

    Jiro Miyamae, Shingo Suzuki, Jerzy K. Kulski & Takashi Shiina

  3. Department of Functional Morphology, Division of Cell Regeneration and Transplantation, Advanced Medical Research Center, Nihon University School of Medicine, 30-1 Ooyaguchikamichou, Itabashi, Tokyo, 173-8610, Japan

    Taro Matsumoto

  4. School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Crawley, WA, 6009, Australia

    Jerzy K. Kulski

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  1. Jiro Miyamae
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Electronic supplementary material

Supplementary figure 1

Nucleotide alignment for DLA-class I cDNA sequences and primer locations. The nucleotide alignment of DLA-class I genes was constructed using DLA-88 (NM_001014767.1), DLA-12 (NM_001014379.1) and DLA-64 (NM_001014378.1) cDNA and DLA-88 L (LC189199) genomic sequences. The DLA-79 cDNA sequence was not included in the alignment due to too many nucleotide differences. 5’UTR, SP, TM, CY and 3’UTR indicate 5′ untranslated region, signal peptide region, transmembrane region, cytoplasmic region and 3′ untranslated region, respectively. Hyphen indicates insertion or deletion site, and asterisk and period indicate matched and mismatched site among three sequences, respectively. Yellow background (around positions 100 bp) indicates sense primers for RT-PCR and genomic analyses, blue background (around positions 630 bp) indicates sense primers for quantitative PCR analysis, and green background (around positions 730 bp) indicates anti-sense primers for RT-PCR, genomic and quantitative PCR analyses. (DOCX 37 kb).

Supplementary figure 2

Inheritance of DLA-class I haplotypes based on DLA-class I cDNA analysis in four beagle families. A total of 38 beagles from four families were used for this study. Colored bars show the DLA haplotypes that are indicated in the table below the four pedigree charts. (PPTX 81 kb).

Supplementary figure 3

Relative gene expression levels of DLA-class I genes in each haplotype. (A) Relative gene expression levels of the DLA-88, DLA-12 and DLA-64 genes of the DLA-88-DLA-12-DLA-64 haplotypes using ten dogs. The DLA-88*501:01-DLA-12*1-DLA-64*nov2 (N = 4), DLA-88*006:01-DLA-12*1-DLA-64*nov2 (N = 3) and DLA-88*012:01-DLA-12*1-DLA-64*nov2 (N = 3) were analyzed. (B) Relative gene expression levels of the DLA-88, DLA-88 L and DLA-64 genes of DLA-88-DLA-88L-DLA-64 haplotypes using 12 dogs. The DLA-88*028:01-DLA-88*029:01-DLA-64*nov2 (N = 3), DLA-88*028:03-DLA-88*029:01-DLA-64*nov2 (N = 3), DLA-88*003:02-DLA-88*017:01-DLA-64*nov2 (N = 3) and DLA-88*nov10-DLA-88*L-DLA-64*nov2 (N = 3) were analyzed. Vertical axis shows the relative quantitative values by the real-time PCR method. Thin bars show standard errors. The vertical bars represent the mean of the relative quantitative values. (PPTX 58 kb).

Supplementary figure 4

Logos of amino acid consensus sequences of T cell recognition sites (TRSs) and peptide binding regions (PBRs) of translated DLA-class I genes. The logos plots were analyzed using 65 allele sequences (58 major and seven minor official alleles) with 45 DLA-88 (41 DLA-88 + four DLA-88*50X), seven DLA-88 L, 11 DLA-12 and two DLA-64 and six released DLA-79 sequences. (A) and (B) show logos for TRSs and PBRs, respectively. The overall height of each stack indicates the amino acid conservation at that position and the height of the letters within each stack indicated the relative frequency of the conforming amino acid at that position (Crooks et al. 2004). The overall height of DLA-64 is underestimated due to the low number of alleles. Yellow box shows an extra residue (leucine, L) in the DLA-88*50X allele group at position 155, which was attributed as part of the TRSs in a recent study (Xiao et al. 2016). Blue, black and green letters indicate hydrophilic, hydrophobic and green neutral amino acid residues, respectively. (PPTX 635 kb).

Supplementary Table 1

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Supplementary Table 2A

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Supplementary Table 2B

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Supplementary Table 3

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Supplementary Table 4

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Supplementary Table 5

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Miyamae, J., Suzuki, S., Katakura, F. et al. Identification of novel polymorphisms and two distinct haplotype structures in dog leukocyte antigen class I genes: DLA-88, DLA-12 and DLA-64 . Immunogenetics 70, 237–255 (2018). https://doi.org/10.1007/s00251-017-1031-5

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