Abstract
Indian rhesus macaque major histocompatibility complex (MHC) variation can influence the outcomes of transplantation and infectious disease studies. Frequently, rhesus macaques are MHC genotyped to identify variants that could account for unexpected results. Since the MHC is only one region in the genome where variation could impact experimental outcomes, strategies for simultaneously profiling variation in the macaque MHC and the remainder of the protein coding genome would be useful. Here we determine MHC class I and class II genotypes using target-capture probes enriched for MHC sequences, a method we term macaque exome sequence (MES) genotyping. For a cohort of 27 Indian rhesus macaques, we describe two methods for obtaining MHC genotypes from MES data and demonstrate that the MHC class I and class II genotyping results obtained with these methods are 98.1% and 98.7% concordant, respectively, with expected MHC genotypes. In contrast, conventional MHC genotyping results obtained by deep sequencing of short multiplex PCR amplicons were only 92.6% concordant with expectations for this cohort.
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Acknowledgments
We gratefully acknowledge Michele Di Mascio and his group at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health for providing rhesus macaque samples used in this study. We also gratefully thank Brian Bushnell for assistance with the BBTools software, and the WNPRC for providing samples from five related macaques.
Funding
This research was supported by contract HHSN272201600007C from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. This work was also supported in part by the Office of Research Infrastructure Programs/OD (P51OD011106) awarded to the Wisconsin National Primate Research Center at the University of Wisconsin-Madison. This research was also supported in part by grant R24-OD011173 from the National Institutes of Health. This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grants RR15459-01 and RR020141-01.
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Supplementary Materials
Supplementary Figure 1
Comparison of MHC class I results from MiSeq PCR amplicon versus whole exome genotyping assays with the DSR and SAVAGE strategies for all 27 animals. Results for each of the three method are provided side-by-side in the columns for each macaque. Each row indicates the detection of a specific MHC class I allele or lineage group of closely related sequences that are ambiguous because they are identical over the IPD exon 2 database sequence. Values in the body of this figure indicate the number of sequence reads supporting each allele call for the MiSeq and DSR methods while alleles supported by a SAVAGE contig are reported with a “1”. Discrepancies between the MiSeq, DSR, or SAVAGE methods are highlighted by magenta-filled cells with borders. Abbreviated Mamu haplotype designations (Karl et al. 2013) for each individual are summarized below the Animal IDs. The Mamu class I and Mamu-DRB alleles that have been associated with each of these abbreviated haplotypes are listed in Supplementary Fig. 2. Color coded cells indicate MHC sequences that are inferred to be associated with extended MHC haplotypes based on segregation in directly related individuals (first five animals) or by shared allele combinations in animals whose pedigree relationships are unknown (final 22 individuals). For example, the twenty MHC sequences (highlighted in red), associated with an extended haplotype that is shared by dam r05029 and her progeny r17099, can be summarized by the following string of abbreviated Mamu haplotype designations: Mamu-A004/B048/DR04a/DQA01g1/DQB06:01/DPA02g1/DPB15g. (XLSX 258 kb)
Supplementary Figure 2
Abbreviated Mamu-A, -B and -DRB haplotype definitions for the animals evaluated in this study. The Mamu-A, -B and -DRB allele lineages that have been associated with each of the 43 abbreviated haplotypes observed in this study are listed here. These abbreviated haplotype designations were originally assigned based on the presence of a major “diagnostic” sequence that was typically the most abundant transcript associated with a haplotype in deep sequencing assays with cDNA templates (Karl et al. 2013). For example, the Mamu-A001 haplotype generally encodes a Mamu-A1*001g2 major transcript along with a minor Mamu-A2*05g1 transcript. (XLSX 11 kb)
Supplementary Figure 3
Example of chimeric PCR amplification. The top panel shows the alignment of three IPD exon 2 reference sequences: Mamu-B20*01 g1 (top, green), Mamu-B*007:07 (middle, blue), Mamu-B*007 g1 (bottom, purple), and the location of the forward and reverse primers, SBT195F and SBT195R (top arrows, gray). The yellow boxes on the sequences represent SNPs between Mamu-B20*01 g1 and Mamu-B*007:07 and between Mamu-B*007 g1 and Mamu-B*007:07. The positions are relative to the end of the forward primer, with SNPs at position 7 and position 96 labeled accordingly. In this example, both Mamu-B20*01 g1 and Mamu-B*007 g1 are evident in the sample. During PCR, Mamu-B20*01 g1 aborts amplification between positions 7 and 96. This aborted amplification becomes a “primer” in the next cycle and continues to amplify using Mamu-B*007 g1 as a template. The resulting chimeric sequence is identical to Mamu-B*007:07 (Fichot and Norman 2013). (PDF 880 kb)
Supplementary Table 1
Fraction of total exome sequence reads corresponding to MHC class I and class II genes after target capture with the VCRom2.1 probe design alone. This exome sequence dataset was described previously by Ericsen and coworkers (Ericsen et al. 2014). (PDF 37 kb)
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Caskey, J.R., Wiseman, R.W., Karl, J.A. et al. MHC genotyping from rhesus macaque exome sequences. Immunogenetics 71, 531–544 (2019). https://doi.org/10.1007/s00251-019-01125-w
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DOI: https://doi.org/10.1007/s00251-019-01125-w