Balancing Selection Maintains a Form of ERAP2 that Undergoes Nonsense-Mediated Decay and Affects Antigen Presentation

Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA.
PLoS Genetics (Impact Factor: 7.53). 10/2010; 6(10):e1001157. DOI: 10.1371/journal.pgen.1001157
Source: PubMed


A remarkable characteristic of the human major histocompatibility complex (MHC) is its extreme genetic diversity, which is maintained by balancing selection. In fact, the MHC complex remains one of the best-known examples of natural selection in humans, with well-established genetic signatures and biological mechanisms for the action of selection. Here, we present genetic and functional evidence that another gene with a fundamental role in MHC class I presentation, endoplasmic reticulum aminopeptidase 2 (ERAP2), has also evolved under balancing selection and contains a variant that affects antigen presentation. Specifically, genetic analyses of six human populations revealed strong and consistent signatures of balancing selection affecting ERAP2. This selection maintains two highly differentiated haplotypes (Haplotype A and Haplotype B), with frequencies 0.44 and 0.56, respectively. We found that ERAP2 expressed from Haplotype B undergoes differential splicing and encodes a truncated protein, leading to nonsense-mediated decay of the mRNA. To investigate the consequences of ERAP2 deficiency on MHC presentation, we correlated surface MHC class I expression with ERAP2 genotypes in primary lymphocytes. Haplotype B homozygotes had lower levels of MHC class I expressed on the surface of B cells, suggesting that naturally occurring ERAP2 deficiency affects MHC presentation and immune response. Interestingly, an ERAP2 paralog, endoplasmic reticulum aminopeptidase 1 (ERAP1), also shows genetic signatures of balancing selection. Together, our findings link the genetic signatures of selection with an effect on splicing and a cellular phenotype. Although the precise selective pressure that maintains polymorphism is unknown, the demonstrated differences between the ERAP2 splice forms provide important insights into the potential mechanism for the action of selection.

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    • "Their role in response to infection would expose them to selective pressure. Consistent with this, Andres and colleagues described signatures of balancing selection in both ERAP1 and ERAP2 across human populations [11]. Differing genotypes of ERAP2 not only affect enzyme levels but also affect the amount of surface MHC molecules. "
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    • "However, a high-frequency variant, when present in homozygosity (about 25% of the population), results in the absence of ERAP2 protein in these individuals. In ERAP2-deficient human B cells, surface MHC-I expression is reduced.32 It remains unclear whether the absence of ERAP2 might alter/modulate antigen presentation in these individuals, especially patients with such diseases as AS and Crohn’s disease in which disease-associated ERAP2 variants exist. "
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