Dataset Information

Characterization of 100 extended major histocompatibility complex haplotypes in Indonesian cynomolgus macaques.

ABSTRACT: Many medical advancements-including improvements to anti-rejection therapies in transplantation and vaccine development-rely on preclinical studies conducted in cynomolgus macaques (Macaca fascicularis). Major histocompatibility complex (MHC) class I and class II genes of cynomolgus macaques are orthologous to human leukocyte antigen complex (HLA) class I and class II genes, respectively. Both encode cell-surface proteins involved in cell recognition and rejection of non-host tissues. MHC class I and class II genes are highly polymorphic, so comprehensive genotyping requires the development of complete databases of allelic variants. Our group used PacBio circular consensus sequencing of full-length cDNA amplicons to characterize MHC class I and class II transcript sequences for a cohort of 293 Indonesian cynomolgus macaques (ICM) in a large, pedigreed breeding colony. These studies allowed us to expand the existing database of Macaca fascicularis (Mafa) alleles by identifying an additional 141 MHC class I and 61 class II transcript sequences. In addition, we defined co-segregating combinations of allelic variants as regional haplotypes for 70 Mafa-A, 78 Mafa-B, and 45 Mafa-DRB gene clusters. Finally, we defined class I and class II transcripts that are associated with 100 extended MHC haplotypes in this breeding colony by combining our genotyping analyses with short tandem repeat (STR) patterns across the MHC region. Our sequencing analyses and haplotype definitions improve the utility of these ICM for transplantation studies as well as infectious disease and vaccine research.

SUBMITTER: Shortreed CG

PROVIDER: S-EPMC7223175 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Characterization of 100 extended major histocompatibility complex haplotypes in Indonesian cynomolgus macaques.

Shortreed Cecilia G CG Wiseman Roger W RW Karl Julie A JA Bussan Hailey E HE Baker David A DA Prall Trent M TM Haj Amelia K AK Moreno Gage K GK Penedo Maria Cecilia T MCT O'Connor David H DH

Immunogenetics 20200229 4

Many medical advancements-including improvements to anti-rejection therapies in transplantation and vaccine development-rely on preclinical studies conducted in cynomolgus macaques (Macaca fascicularis). Major histocompatibility complex (MHC) class I and class II genes of cynomolgus macaques are orthologous to human leukocyte antigen complex (HLA) class I and class II genes, respectively. Both encode cell-surface proteins involved in cell recognition and rejection of non-host tissues. MHC class ...[more]

PMID: 32112172

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Project description:To determine the relationship between highly-conserved extended-haplotypes (CEHs) in the major histocompatibility complex (MHC) and MS-susceptibility.Among the ~200 MS-susceptibility regions, which are known from genome-wide analyses of single nucleotide polymorphisms (SNPs), the MHC accounts for roughly a third of the currently explained variance and the strongest MS-associations are for certain Class II alleles (e.g., HLA-DRB1*15:01; HLA-DRB1*03:01; and HLA-DRB1*13:03), which frequently reside on CEHs within the MHC.Autosomal SNPs (441,547) from 11,376 MS cases and 18,872 controls in the WTCCC dataset were phased. The most significant MS associated SNP haplotype was composed of 11 SNPs in the MHC Class II region surrounding the HLA-DRB1 gene. We also phased alleles at the HLA-A, HLA-C, HLA-B, HLA-DRB1, and HLA-DQB1 loci. This data was used to probe the relationship between CEHs and MS susceptibility.We phased a total of 59,884 extended haplotypes (HLA-A, HLA-C, HLA-B, HLA-DRB1, HLA-DQB1 and SNP haplotypes) from 29,942 individuals. Of these, 10,078 unique extended haplotypes were identified. The 10 most common CEHs accounted for 22% (13,302) of the total. By contrast, the 8,446 least common extended haplotypes also accounted for approximately 20% (12,298) of the total. This extreme frequency-disparity among extended haplotypes necessarily complicates interpretation of reported disease-associations with specific HLA alleles. In particular, the HLA motif HLA-DRB1*15:01~HLA-DQB1*06:02 is strongly associated with MS risk. Nevertheless, although this motif is almost always found on the a1 SNP haplotype, it can rarely be found on others (e.g., a27 and a36), and, in these cases, it seems to have no apparent disease-association (OR = 0.7; CI = 0.3-1.3 and OR = 0.7; CI = 0.2-2.2, respectively). Furthermore, single copy carriers of the a1 SNP-haplotype without this HLA motif still have an increased disease risk (OR = 2.2; CI = 1.2-3.8). In addition, even among the set of CEHs, which carry the Class II motif of HLA-DRB1*15:01~HLA-DQB1*06:02~a1, different CEHs have differing strengths in their MS-associations.The MHC in diverse human populations consists, primarily, of a very small collection of very highly-selected CEHs. Our findings suggest that the MS-association with the HLA-DRB1*15:01~HLA-DQB1*06:02 haplotype may be due primarily to the combined attributes of the CEHs on which this particular HLA-motif often resides.

Dataset Information

Characterization of 100 extended major histocompatibility complex haplotypes in Indonesian cynomolgus macaques.

Publications

Characterization of 100 extended major histocompatibility complex haplotypes in Indonesian cynomolgus macaques.

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