A<i>cis</i>-regulatory element regulates<i>ERAP2</i>expression through autoimmune disease risk SNPs

Venema, Wouter J.; Hiddingh, Sanne; Loosdregt, Jorg van; Balliu, Brunilda; Boer, Joke H. de; Norel, Jeanette Ossewaarde-van; Thompson, Susan D.; Langefeld, Carl D.; Veken, Lars T. van der; Sofiadis, Konstantinos; Krijger, Peter H.L.; Laat, Wouter de; Kuiper, Jonas J.W.

doi:10.1101/2023.03.03.530973

Cited by 3 publications

(1 citation statement)

References 76 publications

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“…The relatively imprecise prediction of T points to selection starting ~2,000 ya, or ~1,000 ya when assuming an onset of selection of 2,000 years in the past at most, a period that includes the Justinian plague and the medieval Black Death pandemics in Europe (Supplementary Figure S11). To confirm, we analyzed the splice region SNP rs2248374, a variant directly controlling the ERAP2 expression (VENEMA et al 2023). Independently of the continental subregion studied and the methods used, we found significant signals of positive selection targeting the allele producing full-size ERAP2 protective against Black Death, with CNN predictions also pointing to recent selection starting ~2,000 ya (Supplementary Figure S12).…”

Section: Detecting Selection At the Subcontinental Scalementioning

confidence: 94%

Deep estimation of the intensity and timing of selection from ancient genomes

Laval

Patin

Kerner

2023

Preprint

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Leveraging past allele frequencies has proven to be key to identify the impact of natural selection across time. However, this approach often suffers from imprecise estimations of the intensity (s) and timing (T) of selection particularly when ancient samples are scarce in specific epochs. Here, we aimed at bypassing the computation of past allele frequencies by implementing new convolutional neural networks (CNNs) algorithms that directly use ancient genotypes sampled across time to refine the estimations of selection parameters. Using computer simulations, we first show that genotype-based CNNs consistently outperform an approximate Bayesian computation (ABC) approach based on past allele frequency trajectories, regardless of the selection model assumed and of the amount of ancient genotypes available. When applying this method to empirical data from modern and ancient Europeans, we confirmed the reported excess of selection events in post-Neolithic Europe, independently of the continental subregion studied. Furthermore, we substantially refined the ABC-based estimations of s and T for a set of positively- and negatively-selected variants recently identified, including iconic cases of positive selection and experimentally validated disease-risk variants. Thanks to our CNN predictions we provide support to the history of recent and strong selection in northern Europe associated to the Black Death pandemic and confirm the heavy burden recently imposed by tuberculosis in Europe. These findings collectively support that detecting the imprints of natural selection on ancient genomes are crucial for unraveling the past history of severe human diseases.

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Section: Detecting Selection At the Subcontinental Scalementioning

confidence: 94%

Deep estimation of the intensity and timing of selection from ancient genomes

Laval

Patin

Kerner

2023

Preprint

View full text Add to dashboard Cite

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Evolutionary immuno-genetics of endoplasmic reticulum aminopeptidase II (ERAP2)

Raja,

Kuiper

2023

Genes Immun

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Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a proteolytic enzyme involved in adaptive immunity. The ERAP2 gene is highly polymorphic and encodes haplotypes that confer resistance against lethal infectious diseases, but also increase the risk for autoimmune disorders. Identifying how ERAP2 influences susceptibility to these traits requires an understanding of the selective pressures that shaped and maintained allelic variation throughout human evolution. Our review discusses the genetic regulation of haplotypes and diversity in naturally occurring ERAP2 allotypes in the global population. We outline how these ERAP2 haplotypes evolved during human history and highlight the presence of Neanderthal DNA sequences in ERAP2 of modern humans. Recent evidence suggests that human adaptation during the last ~10,000 years and historic pandemics left a significant mark on the ERAP2 gene that determines susceptibility to infectious and inflammatory diseases today.

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The effect of rs2910686 on ERAP2 expression in IBD and epithelial inflammatory response

Sæterstad,

Østvik,

Hansen

et al. 2024

J Transl Med

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Background ERAP2 is an aminopeptidase involved in antigen processing and presentation, and harbor genetic variants linked to several inflammatory diseases such as Inflammatory Bowel Disease (IBD). The lack of an ERAP2 gene homologue in mice has hampered functional studies, and most human studies have focused on cells of hematopoietic origin. Using an IBD biobank as vantage point, this study explores how genetic variation in ERAP2 affects gene expression in human-derived epithelial organoids upon proinflammatory stimulation. Methods An IBD patient cohort was genotyped with regards to two single nucleotide polymorphisms (SNP) (rs2910686/rs2248374) associated with ERAP2 expression levels, and we examined the correlation between colon gene expression and genotype, specifically aiming to establish a relationship with ERAP2 expression proficiency. Human-derived colon organoids (colonoids) with known ERAP2 genotype were established and used to explore differences in whole genome gene expression between ERAP2-deficient (n = 4) and -proficient (n = 4) donors upon pro-inflammatory encounter. Results When taking rs2910686 genotype into account, ERAP2 gene expression is upregulated in the inflamed colon of IBD patients. Colonoids upregulate ERAP2 upon IFNɣ stimulation, and ERAP2 expression proficiency is dependent on rs2910686 genotype. Colonoid genotyping confirms that mechanisms independent of the frequently studied SNP rs2248374 can cause ERAP2-deficiency. A total of 586 genes involved in various molecular mechanisms are differentially expressed between ERAP2 proficient- and deficient colonoids upon proinflammatory stimulation, including genes encoding proteins with the following molecular function: catalytic activity (AOC1, CPE, ANPEP and MEP1A), regulator activity (TNFSF9, MDK, GDF15, ILR6A, LGALS3 and FLNA), transmembrane transporter activity (SLC40A1 and SLC5A1), and extracellular matrix structural constituents (FGL2, HMCN2, and MUC17). Conclusions ERAP2 is upregulated in the inflamed IBD colon mucosa, and expression proficiency is highly correlated with genotype of rs2910686. While the SNP rs2248374 is commonly used to determine ERAP2 expressional proficiency, our data confirms that mechanisms independent of this SNP can lead to ERAP2 deficiency. Our data demonstrates that epithelial ERAP2 presence affects the inflammatory response in colonoids, suggesting a pleiotropic role of ERAP2 beyond MHC class I antigen processing.

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Acis-regulatory element regulatesERAP2expression through autoimmune disease risk SNPs

Cited by 3 publications

References 76 publications

Deep estimation of the intensity and timing of selection from ancient genomes

Deep estimation of the intensity and timing of selection from ancient genomes

Evolutionary immuno-genetics of endoplasmic reticulum aminopeptidase II (ERAP2)

The effect of rs2910686 on ERAP2 expression in IBD and epithelial inflammatory response

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