Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation.
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.
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. aida.andres@eva.mpg.de
Aida M
AM
Andrés
Megan Y
MY
Dennis
Warren W
WW
Kretzschmar
Jennifer L
JL
Cannons
Shih-Queen
SQ
Lee-Lin
Belen
B
Hurle
Pamela L
PL
Schwartzberg
Scott H
SH
Williamson
Carlos D
CD
Bustamante
Rasmus
R
Nielsen
Andrew G
AG
Clark
Eric D
ED
Green
D000626:Aminopeptidases / Q000235:genetics* / Q000276:immunology; D017951:Antigen Presentation; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D005787:Gene Frequency; D005828:Genetics, Population; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007198:Indians, North American / Q000235:genetics; D015778:Minor Histocompatibility Antigens; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D014176:Protein Biosynthesis; D012323:RNA Processing, Post-Transcriptional; D012326:RNA Splicing; D012641:Selection, Genetic; D044465:White People / Q000235:genetics
D015395:Histocompatibility Antigens Class I; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human