Variation in the Untranslated Genome and Susceptibility to Infections

Abstract

The clinical outcomes of infections are highly variable among individuals and are determined by complex host-pathogen interactions. Genome-wide association studies (GWAS) are powerful tools to unravel common genetic variations that are associated with disease risk and clinical outcomes. However, GWAS has only rarely revealed information on the exact genetic elements and their effects underlying an association because the majority of the hits are within non-coding regions. Some of the variants or the linked polymorphisms are now being discovered to have functional significance, such as regulatory elements in the promoter and enhancer regions or the microRNA binding sites in the 3′untranslated region of the protein-coding genes, which influence transcription, RNA stability, and translation of the protein-coding genes. However, only 3% of the entire transcriptome is protein-coding, signifying that non-coding RNAs represent most of the transcripts. Thus, a large portion of previously identified intergenic GWAS single nucleotide polymorphisms (SNPs) is in the non-coding RNAs. The non-coding RNAs form a large-scale regulatory network across the transcriptome, greatly expanding the complexity of gene regulation. Accumulating evidence also suggests that the “non-coding” genome regions actively regulate the highly dynamic three dimensional (3D) chromatin structures, which are critical for genome function. Epigenetic modulation like DNA methylation and histone modifications further affect chromatin accessibility and gene expression adding another layer of complexity to the functional interpretation of genetic variation associated with disease outcomes. We provide an overview of the current information on the influence of variation in these “untranslated” regions of the human genome on infectious diseases. The focus of this review is infectious disease-associated polymorphisms and gene regulatory mechanisms of pathophysiological relevance.

Loci Associated With Antibody Response in Feral Swine (Sus scrofa) Infected With Brucella suis

“…′ UTR, and expression of long non-coding RNAs [lncRNA; (144)(145)(146)(147)]. Studies suggest that changes in gene expression can dysregulate immune pathways that are fundamental in disease outcomes (146,148).…”

Impact of rare and common genetic variation in the interleukin-1 pathway on human cytokine responses

“…Accumulating evidence highlights a role for common non-coding genetic variation in human health [38,39], in inflammatory responses [45,46], and even specifically in innate immune responses [47][48][49]. While the rest of our study focused on coding variants, i.e., variants that likely have a direct effect on protein function, we therefore additionally aimed to gain insight into the impact of non-coding common variants.…”

Disease-Causing Mutations and Rearrangements in Long Non-coding RNA Gene Loci

“…Thus, it is not surprising, that several lncRNAs with disease-associated polymorphisms were implicated at the intersection of these three leading causes of death. Examples include NEAT1, Gas5, or ANRIL (see above), but also H19, LINC00305 and various other lncRNAs (Giral et al, 2018;Minotti et al, 2018;Ramsuran et al, 2018;Castellanos-Rubio and Ghosh, 2019). Besides these three major human health burdens, lncRNA SNPs have also been associated with rather rare disorders, such as HELLP (hemolysis, elevated liver enzymes, and low platelets).…”