Abstract
The major histocompatibility complex (MHC) contains many genes that play key roles in initiating and regulating immune responses. This includes the polymorphic MHCI and MHCII genes that present epitopes to CD8+ and CD4+ T-cells, respectively. Consequently, the characterisation of the repertoire of MHC genes is an important component of improving our understanding of the genetic variation that determines the outcomes of immune responses. In cattle, MHC (BoLA) research has predominantly focused on Holstein-Friesian animals (as the most economically important breed globally), although the development of high-throughput approaches has allowed the BoLA-DRB3 repertoire to be studied in a greater variety of breeds. In a previous study we reported on the development of a MiSeq-based method to enable high-throughput and high-resolution analysis of bovine MHCI repertoires. Herein, we report on the expansion of this methodology to incorporate analysis of the BoLA-DRB3 and its application to analyse MHC diversity in a large cohort of cattle from Brazil (>500 animals), including representatives from the three major Bos indicus breeds present in Brazil - Guzerat, Gir and Nelore. This large-scale description of paired MHCI-DRB3 repertoires in Bos indicus cattle has identified a small number of novel DRB3 alleles, a large number of novel MHCI alleles and haplotypes, and provided novel insights into MHCI-MHCII association - further expanding our knowledge of bovine MHC diversity.
Highlights
The Major Histocompatibility (MHC) locus contains a large number of genes associated with antigen presentation, including the MHCI and MHCII genes, which have a primary function in presenting peptide antigens to CD8+
In this study we report on the expansion of the MiSeq protocol to include analysis of DRB3 and apply this to analysis of >500 animals of predominantly Bos indicus breeds of cattle in Brazil
Our results have identified a large number of new bovine MHCI alleles and haplotypes and by conducting large scale parallel sequencing of MHCI and DRB3, have provided novel insights into the associations between MHCI and MHCII genes in cattle
Summary
The Major Histocompatibility (MHC) locus contains a large number of genes associated with antigen presentation, including the MHCI and MHCII genes, which have a primary function in presenting peptide antigens to CD8+. Both the MHCI and MHCII genes are characterised by a high level of polymorphic diversity; for example, in humans >18,000 MHCI and > 7000 MHCII alleles have been identified (IPD-MHC database January 2020-https://www.ebi.ac.uk/ipd/1). Most of this polymorphism is focused within the exons. There are multiple isotypes of MHCII molecules (e.g. in humans there are DR, DQ and DP MHCII molecules), each of which are heterodimers composed of α and β chains and function predominantly in the presentation of peptides to CD4+ T-cells Both chains are made up of two extra-cellular domains (α1/α2 and β1/β2, respectively), containing alpha helices similar to those in MHCI, a transmembrane region and an intra-cytoplasmic domain. Our results have identified a large number of new bovine MHCI alleles and haplotypes and by conducting large scale parallel sequencing of MHCI and DRB3, have provided novel insights into the associations between MHCI and MHCII genes in cattle
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