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

Andrés, Aida M.; Dennis, Megan Y.; Kretzschmar, Warren W.; Cannons, Jennifer L.; Lee-Lin, Shih-Queen; Hurlé, Belén; Program, Nisc Comparative Sequencing; Schwartzberg, Pamela L.; Williamson, Scott; Bustamante, Carlos D.; Nielsen, Rasmus; Clark, Andrew G.; Green, Eric D.

doi:10.1371/journal.pgen.1001157

Cited by 221 publications

(307 citation statements)

References 85 publications

(99 reference statements)

Supporting

Mentioning

293

Contrasting

Unclassified

Order By: Relevance

“…The allelic ratios were greater than 0.8 for all of these genes. However, several studies have reported the alteration of ERAP2 expression by nonsense-mediated decay 47,48 which may adversely affect the imprinting status for this gene. Ultimately, we identified four putative imprinted coding genes (ADTRP, ATP5EP2, SMOC1, PRIM2) and five polyadenylated (sno)RNAs in the known imprinted 14q32 region.…”

Section: Identification Of Putative Imprinted Genes In Primary Singlementioning

confidence: 99%

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

Santoni

Stamoulis

Garieri

et al. 2017

The American Journal of Human Genetics

View full text Add to dashboard Cite

Genomic imprinting results in parental-specific gene expression. Imprinted genes are involved in the etiology of rare syndromes and have been associated with common diseases such as diabetes and cancer. Standard RNA bulk cell sequencing applied to whole-tissue samples has been used to detect imprinted genes in human and mouse models. However, lowly expressed genes cannot be detected by using RNA bulk approaches. Here, we report an original and robust method that combines single-cell RNA-seq and whole-genome sequencing into an optimized statistical framework to analyze genomic imprinting in specific cell types and in different individuals. Using samples from the probands of 2 family trios and 3 unrelated individuals, 1,084 individual primary fibroblasts were RNA sequenced and more than 700,000 informative heterozygous single-nucleotide variations (SNVs) were genotyped. The allele-specific coverage per gene of each SNV in each single cell was used to fit a beta-binomial distribution to model the likelihood of a gene being expressed from one and the same allele. Genes presenting a significant aggregate allelic ratio (between 0.9 and 1) were retained to identify of the allelic parent of origin. Our approach allowed us to validate the imprinting status of all of the known imprinted genes expressed in fibroblasts and the discovery of nine putative imprinted genes, thereby demonstrating the advantages of single-cell over bulk RNA-seq to identify imprinted genes. The proposed single-cell methodology is a powerful tool for establishing a cell type-specific map of genomic imprinting.

show abstract

Section: Identification Of Putative Imprinted Genes In Primary Singlementioning

confidence: 99%

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

Santoni

Stamoulis

Garieri

et al. 2017

The American Journal of Human Genetics

View full text Add to dashboard Cite

show abstract

“…In the worldwide population, evolution under balancing selection has maintained two main ERAP2 haplotypes: one expressing the protein and the other ERAP2-deficient, because the G allelic variant of SNP rs2248374 induces a truncated form that goes through non-sense-mediated decay [84]. The two haplotypes are almost equally frequent in the different ethnic groups, so that 25% of individuals, being homozygous for the second haplotype, do not express ERAP2.…”

Section: Hla-b27 a Molecule With Two Faces: Protection From Viral Inmentioning

confidence: 99%

“…This functional variant is in strong linkage with SNP rs2248374. Apart from specific ethnic peculiarities, the N392 allelic variant is almost absent in the human populations because of its co-inheritance with the rs2248374 null-allele [84,85].…”

Section: Hla-b27 a Molecule With Two Faces: Protection From Viral Inmentioning

confidence: 99%

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

Vitulano

Tedeschi

Paladini

et al. 2017

Clinical and Experimental Immunology

View full text Add to dashboard Cite

1These authors contributed equally to this study. SummaryThe human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

show abstract

“…Supposing that some balancing selection occurs within a genome, one might locate candidate genes by identifying shared alleles between closely related species (Asthana et al 2005), by finding gene genealogies with exceptionally long internal branches compared to the rest of the genome Hudson and Kaplan 1988;Charlesworth and Charlesworth 2010), or by finding genomic regions with an excess abundance of sites with intermediate allele frequency (Andrés et al 2009(Andrés et al , 2010. To date, such loci appear to be exceedingly rare, which is taken to mean that: (i) balancing selection rarely occurs, or (ii) balancing selection is too temporally fleeting to leave a recognizable pattern in the molecular data.…”

Section: The Maintenance Of Fitness Variation By Antagonistic Selectionmentioning

confidence: 99%

A General Population Genetic Framework for Antagonistic Selection That Accounts for Demography and Recurrent Mutation

2012

View full text Add to dashboard Cite

Antagonistic selection-where alleles at a locus have opposing effects on male and female fitness ("sexual antagonism") or between components of fitness ("antagonistic pleiotropy")-might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range-a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The "efficacy" of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (N e s .. 1, where N e is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection. P LEIOTROPY may impose widespread evolutionary genetic constraints against adaptation (Fisher 1958, Orr 1998, Otto 2004. Allocation tradeoffs between fitness components, coupled with a shared genetic basis between them, may limit evolutionary opportunities to simultaneously maximize individual components of fitness (Houle 1991). Conflicting selection may emerge at underlying loci, so that alleles improving one fitness component reduce othersa scenario referred to as "antagonistic pleiotropy" (Rose 1982;Curtsinger et al. 1994). A similar scenario arises when patterns of selection differ between males and females. Opposing, sex-specific selection, or "sexual antagonism," arises when mutations favorable within one sex are costly when expressed in the other Bonduriansky and Chenoweth 2009;van Doorn 2009).Antagonistic selection may play an important role in maintaining genetic variation related to fitness and driving patterns of genome evolution. Direct estimates of sex-and context-specific selection on quantitative traits confirm that pleiotropic and sexually antagonistic fitness tradeoffs are ubiquitous (Curtsinger et al. 1994;Roff 1996;Delph 2007;Cox and Calsbeek 2009;Poissant and Coltma...

show abstract

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

Cited by 221 publications

References 85 publications

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

Detection of Imprinted Genes by Single-Cell Allele-Specific Gene Expression

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

A General Population Genetic Framework for Antagonistic Selection That Accounts for Demography and Recurrent Mutation

Contact Info

Product

Resources

About