Introgression from domestic goat generated variation at the major histocompatibility complex of Alpine ibex.

Daniel Croll,Lukas Keller,Iris Biebach,Mikkel H Schierup,Christine Grossen

doi:10.1371/journal.pgen.1004438

Abstract

The major histocompatibility complex (MHC) is a crucial component of the vertebrate immune system and shows extremely high levels of genetic polymorphism. The extraordinary genetic variation is thought to be ancient polymorphisms maintained by balancing selection. However, introgression from related species was recently proposed as an additional mechanism. Here we provide evidence for introgression at the MHC in Alpine ibex (Capra ibex ibex). At a usually very polymorphic MHC exon involved in pathogen recognition (DRB exon 2), Alpine ibex carried only two alleles. We found that one of these DRB alleles is identical to a DRB allele of domestic goats (Capra aegagrus hircus). We sequenced 2489 bp of the coding and non-coding regions of the DRB gene and found that Alpine ibex homozygous for the goat-type DRB exon 2 allele showed nearly identical sequences (99.8%) to a breed of domestic goats. Using Sanger and RAD sequencing, microsatellite and SNP chip data, we show that the chromosomal region containing the goat-type DRB allele has a signature of recent introgression in Alpine ibex. A region of approximately 750 kb including the DRB locus showed high rates of heterozygosity in individuals carrying one copy of the goat-type DRB allele. These individuals shared SNP alleles both with domestic goats and other Alpine ibex. In a survey of four Alpine ibex populations, we found that the region surrounding the DRB allele shows strong linkage disequilibria, strong sequence clustering and low diversity among haplotypes carrying the goat-type allele. Introgression at the MHC is likely adaptive and introgression critically increased MHC DRB diversity in the genetically impoverished Alpine ibex. Our finding contradicts the long-standing view that genetic variability at the MHC is solely a consequence of ancient trans-species polymorphism. Introgression is likely an underappreciated source of genetic diversity at the MHC and other loci under balancing selection.

Highlights

The major histocompatibility complex (MHC) is one of the most gene-dense regions and contains the most polymorphic functional genes in vertebrate genomes [1,2,3]
We show that introgression from domestic goat dramatically increased genetic variation at the MHC of Alpine ibex, a species that had nearly gone extinct during the 18th century, but has been restored to large numbers since
We extended the sequencing by Schaschl et al [27] and Alasaad et al [28] from 125 to 203 Alpine ibex from different populations and did not find additional alleles at the exon 2 of the MHC DRB locus

Summary

Introduction

The MHC is one of the most gene-dense regions and contains the most polymorphic functional genes in vertebrate genomes [1,2,3]. A higher allelic diversity at MHC loci is expected to be favored because individuals with a broader range of MHC sequences (binding and presenting a broader range of pathogenic peptides) should be able to more successfully fight diseases. Three types of balancing selection, mediated by pathogen-driven or sexual selection, are usually invoked to explain MHC polymorphism: heterozygote advantage, negative frequency-dependent selection and fluctuating selection [11,13]. Linked recessive deleterious mutations may contribute to a pattern of balancing selection and may explain why MHC alleles are frequently more highly diverged from each other than expected otherwise [12]. While MHC alleles often exhibit high sequence divergence, balancing selection tends to even out allele frequencies among populations and such loci show lower population differentiation than neutral loci [14]

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Conclusion