Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation

Aida M. Andrés, Megan Dennis, Warren W. Kretzschmar, Jennifer L. Cannons, Shih Queen Lee-Lin, Belen Hurle, Pamela L. Schwartzberg, Scott H. Williamson, Carlos D. Bustamante, Rasmus Nielsen, Andrew G. Clark, Eric D. Green

Research output: Contribution to journalArticle

121 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1001157
Pages (from-to)1-13
Number of pages13
JournalPLoS Genetics
Volume6
Issue number10
DOIs
StatePublished - Oct 1 2010
Externally publishedYes

Fingerprint

antigen presentation
Aminopeptidases
aminopeptidases
major histocompatibility complex
Antigen Presentation
antigen
Endoplasmic Reticulum
endoplasmic reticulum
Major Histocompatibility Complex
deterioration
Haplotypes
haplotypes
mechanism of action
Nonsense Mediated mRNA Decay
Genetic Selection
immune response
natural selection
Homozygote
homozygosity
phenotype

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Andrés, A. M., Dennis, M., Kretzschmar, W. W., Cannons, J. L., Lee-Lin, S. Q., Hurle, B., ... Green, E. D. (2010). Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. PLoS Genetics, 6(10), 1-13. [e1001157]. https://doi.org/10.1371/journal.pgen.1001157

Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. / Andrés, Aida M.; Dennis, Megan; Kretzschmar, Warren W.; Cannons, Jennifer L.; Lee-Lin, Shih Queen; Hurle, Belen; Schwartzberg, Pamela L.; Williamson, Scott H.; Bustamante, Carlos D.; Nielsen, Rasmus; Clark, Andrew G.; Green, Eric D.

In: PLoS Genetics, Vol. 6, No. 10, e1001157, 01.10.2010, p. 1-13.

Research output: Contribution to journalArticle

Andrés, AM, Dennis, M, Kretzschmar, WW, Cannons, JL, Lee-Lin, SQ, Hurle, B, Schwartzberg, PL, Williamson, SH, Bustamante, CD, Nielsen, R, Clark, AG & Green, ED 2010, 'Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation', PLoS Genetics, vol. 6, no. 10, e1001157, pp. 1-13. https://doi.org/10.1371/journal.pgen.1001157
Andrés, Aida M. ; Dennis, Megan ; Kretzschmar, Warren W. ; Cannons, Jennifer L. ; Lee-Lin, Shih Queen ; Hurle, Belen ; Schwartzberg, Pamela L. ; Williamson, Scott H. ; Bustamante, Carlos D. ; Nielsen, Rasmus ; Clark, Andrew G. ; Green, Eric D. / Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation. In: PLoS Genetics. 2010 ; Vol. 6, No. 10. pp. 1-13.
@article{98b779aa00314885a9d913b05eb9f742,
title = "Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation",
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.",
author = "Andr{\'e}s, {Aida M.} and Megan Dennis and Kretzschmar, {Warren W.} and Cannons, {Jennifer L.} and Lee-Lin, {Shih Queen} and Belen Hurle and Schwartzberg, {Pamela L.} and Williamson, {Scott H.} and Bustamante, {Carlos D.} and Rasmus Nielsen and Clark, {Andrew G.} and Green, {Eric D.}",
year = "2010",
month = "10",
day = "1",
doi = "10.1371/journal.pgen.1001157",
language = "English (US)",
volume = "6",
pages = "1--13",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "10",

}

TY - JOUR

T1 - Balancing selection maintains a form of ERAP2 that undergoes nonsense-mediated decay and affects antigen presentation

AU - Andrés, Aida M.

AU - Dennis, Megan

AU - Kretzschmar, Warren W.

AU - Cannons, Jennifer L.

AU - Lee-Lin, Shih Queen

AU - Hurle, Belen

AU - Schwartzberg, Pamela L.

AU - Williamson, Scott H.

AU - Bustamante, Carlos D.

AU - Nielsen, Rasmus

AU - Clark, Andrew G.

AU - Green, Eric D.

PY - 2010/10/1

Y1 - 2010/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=78449233933&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78449233933&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1001157

DO - 10.1371/journal.pgen.1001157

M3 - Article

C2 - 20976248

AN - SCOPUS:78449233933

VL - 6

SP - 1

EP - 13

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 10

M1 - e1001157

ER -