The evolution and maintenance of polymorphism in the major histocompatibility complex

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Abstract

Lambs with the G2 allele at the ovine major histocompatibility complex (mhc) class II locus DRB1 has previously been shown to have lower faecal nematode egg counts than lambs with the I allele at this locus. This association has been confirmed in separate cohorts from the same farm. Other alleles within the mhc have also shown associations with nematode resistance in other breeds of sheep. Therefore, variation in the mhc is responsible for part of the observed genetic variation in resistance to nematode infection. In addition to the specific effect of particular alleles, heterozygotes are also more resistant than homozygotes. This heterozygote advantage is capable of maintaining the high levels of polymorphism observed within the mhc.

Introduction

The classical loci of the major histocompatibility complex (mhc) encode glycoproteins that present parasite-derived peptides to receptors on T lymphocytes. The peptides that are presented determine the specificity of the acquired immune response (Klein and O’hUigin, 1994). There are a large number of alleles at these loci and the alleles often differ at multiple nucleotides. Mhc variation contributes to differences among individuals in immune responsiveness and disease resistance (Hedrick, 2002). Mhc diversity is probably maintained by balancing selection (Hughes and Yeager, 1998), although there is no consensus on the precise mechanisms. The major candidates are heterozygote advantage, frequency-dependent selection and selection that varies in time or space (Hedrick, 2002). Here, we describe how natural parasite infection maintains mhc polymorphism.

The host–parasite system that we studied was natural nematode infection in sheep. Nematodes are endemic in higher vertebrates and are known to influence host population dynamics in sheep (Moorcroft et al., 1996) and grouse (Hudson et al., 1998). In temperate areas, such as the UK, the dominant nematode of sheep is Teladorsagia circumcincta (Stear et al., 1998) and this is among the best understood of all parasite–host interactions (Grenfell et al., 1995). The genetic basis of resistance, the immune mechanisms involved and the pathogenesis of disease have been recently reviewed (Stear et al., 1997, Stear et al., 1999, Stear et al., 2003). Other advantages of this system are that large numbers of lambs of known pedigree and history of nematode exposure are readily available. Further, statistical methods developed by animal breeders can be used to study mhc effects while simultaneously accounting for the effects of background genes and other known effects, such as year or sex. Importantly, previous results have demonstrated that lambs with specific mhc alleles had lower egg counts than their contemporaries (Schwaiger et al., 1995) and this has been independently confirmed (Paterson et al., 1998, Charon et al., 2002).

Section snippets

Animals

All sheep were straightbred Scottish Blackface sheep from a commercial upland farm in Southwest Strathclyde. All husbandry procedures followed normal, commercial practice and have been described previously (Stear et al., 1998). All lambs were kept on the same field after weaning at 3 or 4 months of age until the end of the study. Previous analyses have shown that genetic variation is only apparent in lambs that are at least 3 months old consistent with the hypothesis that resistance is due to

Results

In this study, lambs with the G2 allele at the DRB1 locus had significantly lower faecal nematode egg counts than lambs with the I allele in September (p < 0.05), confirming the original association (Schwaiger et al., 1995). The impact of substituting one copy of the G2 allele for one copy of the most common allele (I) would be to lower faecal nematode egg counts about 40%. The allele G2 was present in 200/788 lambs for an allele frequency of 12.7%. The analysis accounted for variation among

Discussion

The selection process described here is simple but robust; it will maintain advantageous alleles at intermediate frequencies and also maintain multiple alleles at each locus. In populations with a small number of alleles there will be a relatively high proportion of homozygotes. Recent mutations will occur predominantly in heterozygotes and if these are better than the existing mixture of homozygotes and heterozygotes they will increase in frequency, even if they are no better than existing

Acknowledgements

We thank S. Mitchell, D. Gostomski and P. Feichtlbauer-Huber for assistance with DNA typing.

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