Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk

Abstract

Multiple Sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R), produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5′ UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

“…Specifically, inheritance of the risk allele (C) disrupts a splicing acceptor site and results in transcriptional skipping of exon 6 of the gene, thus altering the relative amounts of soluble and membrane bound isoforms of the gene [58]. More recently, several SNPs within the RNA helicase DEAD box polypeptide 39B (DDX39B) gene were shown to be associated with MS risk in a meta-analysis [59]. In particular, rs2523506-A --located within the 5’UTR of this gene-- was shown to reduce mRNA translation of DDX39B, which is in turn, a potent activator of IL7R exon 6 transcription.…”

The Genetics of Multiple Sclerosis

“…This SNP was shown to disrupt an exonic splicing silencer, affecting the relative amounts of soluble and membranebound isoforms of the protein (25). Recent evidence has shown that the RNA helicase DEAD box polypeptide 39B (DDX39B) is also a potent activator of IL7R exon 6, and the SNP rs2523506 located in the DDX39B 5'UTR increases MS risk by reducing DDX39B mRNA translation (26). A similar effect was described for the intronic SNP rs2104286 in the IL2RA gene as well.…”

Characterising the genetic basis of immune response variation to identify causal mechanisms underlying disease susceptibility

“…For instance, the Multiple sclerosis associated variant rs6897932, located within an exon 6 of IL7R, has been shown to promote exon skipping. As a result, a soluble form of IL7R is being produced that is associated with exacerbated auto‐immune phenotypes in mice . However, despite evidence that 90% of auto‐immune loci act through regulatory variants, 60% of which are located at enhancers, it was suggested that only a limited fraction of the QTLs detected at GWAS loci play a causal role in disease susceptibility .…”

“…In addition, sQTLs displayed a stronger overlap between conditions of stimulation than eQTLs, 11,70 suggesting a limited impact of stimulation on the genetic regulation of splicing. Nevertheless, disease-causing sQTL have been observed at many key immune genes including OAS1, IRF7, IL7R, IFI44L, TYK2, and ERAP2, 11,70,[72][73][74] highlighting the importance of considering splicing variation when searching for the causal mechanisms underlying GWAS loci. Interestingly, several of these loci, including OAS1 or ERAP2 present haplotypic signatures of positive and balancing selection, suggesting that these sQTL have conferred a selective advantage to human populations in the past, likely through increased resistance to pathogens.…”