Constraints on haplotype structure and variable gene frequencies suggest a functional hierarchy within cattle MHC class I

Abstract

Six major histocompatibility complex (MHC) classical class I genes have been identified in cattle, and up to three of these are expressed in variable combinations on different haplotypes. The origin and functional significance of this genetic complexity is unknown. However, an improved assembly of the cattle genome, an expanded database of full-length cDNA sequences and high-resolution frequency data concerning expressed class I genes in an economically important cattle breed combine to provide a new opportunity to study the significance of cattle MHC class I diversity. Analysis of these new data supports assignment of alleles to six discrete genes and further shows that all these classical genes share a common ancestor with a single non-classical gene, NC1. While haplotype structure is variable, with thirteen gene configurations identified, there are nevertheless clear constraints relating to both the number and combination of genes. Haplotypes expressing two classical genes are most frequently observed, and the classical class I gene 2 is almost invariably present. The frequency data support the dominance of gene 2, showing that close to 100 % of individuals carry at least one copy. This indicates a hierarchy in the functional importance of particular genes and haplotype structures. Haplotype frequency in cattle populations is therefore likely to impact on differential disease susceptibilities. This knowledge will be important for development of informed breeding strategies aimed at increasing the ability of cattle to survive in the face of future unpredictable pathogen exposure.

Cattle MHC nomenclature: is it possible to assign sequences to discrete class I genes?

“…It remains a possibility that sequences assigned to genes 1 and 6 may not in fact derive from discrete genes; the gene 6 group may simply represent a divergent lineage. However, in the previous analysis (Codner et al 2012), the sequences assigned to gene 6 grouped more closely with the second large group, dominated by gene 3, supporting their assignment to a discrete gene. In addition, the unique structural and potentially functional characteristics of class I molecules encoded by the gene 6 group of sequences (Macdonald et al 2010) supports their definition as a separate group for the purposes of nomenclature.…”

“…It is clear that inclusion of additional sequences from both Holstein-Friesian and other breeds has reduced the resolution between the putative gene groups, as shown in Codner et al (2012), and also reduced node support. The overall pattern is similar, however, with two clearly segregating groups; one encompasses putative genes 1, 2 and 6 and the second encompasses putative genes 3, 4 and 5.…”

“…This is discussed in detail in Codner et al (2012). Assembling the MHC class I region using DNA from a range of MHC homozygous animals may ultimately clarify the situation.…”

“…A recent study set out to assess functional distinctions between the cattle class I genes, by reference to an expanded database of cattle MHC class I cDNA sequences, the cattle genome and a set of high-resolution frequency data (Codner et al 2012). At the time of that study, there were 80 available class I sequences (compared to the current 114) that segregated into six reasonably well-supported groups after phylogenetic analysis.…”

“…Cattle demonstrate region configuration polymorphism in the MHC. In the case of class I, between one and three of the proposed six classical genes are expressed on any haplotype (Ellis et al 1999;Birch et al 2006;Codner et al 2012).…”