Abstract
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.
Highlights
Balancing selection maintains advantageous genetic diversity in populations
The major histocompatibility complex (MHC) encodes for molecules required for a type of antigen presentation that mediates detection of infected and cancerous cells by the immune system; the genetic diversity of the MHC ensures an adequate response to the wide variety of pathogens that humans encounter
We show that balancing selection acts to maintain two forms of the endoplasmic reticulum aminopeptidase 2 gene (ERAP2), which encodes a protein involved in antigen presentation
Summary
Balancing selection maintains advantageous genetic diversity in populations. Unlike positive and purifying selection, which favor fixation of the fittest allele, balancing selection results in enhanced genetic and phenotypic variability in populations. All of these processes leave the characteristic genetic footprint of balancing selection: an excess of polymorphism due to the long-term maintenance of selected alleles, and an enrichment of variants with a frequency close to the frequency equilibrium (for example, an enrichment in variants at intermediate frequency if the optimal frequency of the selected variant is 0.5). Discerning the biological processes underlying balancing selection remains a challenge, even for loci with striking genetic signatures. There are few well-characterized examples of balancing selection in humans, with both clear genetic signatures and a known biological mechanism for the action of selection.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
