Natural variation in C. elegans genomic defense mechanisms mediated by small RNAs
Authors: Gaotian ZHANG; Erik Andersen
Affiliation: Northwestern University
Keywords: Complex traits
RNA interference is an evolutionarily conserved mechanism for endogenous gene regulation and defense against foreign RNA viruses. Natural variation in exogenous and endogenous RNA interference in Caenorhabditis elegans has been suggested to be genetically complex, but the underlying causal variants are largely unknown. Our recent work revealed gene expression variation and possible regulatory mechanisms across 207 genetically distinct wild C. elegans strains using genome-wide association mappings. We classified expression quantitative trait loci (eQTL) into local eQTL (located close to the genes that they influence) and distant eQTL (located further away from the genes that they influence). We also identified a diverse collection of genomic hotspots enriched for distant eQTL of multiple genes. Here, we investigated the role of small RNAs in eQTL hotspots. We performed gene set enrichment analysis on genes with eQTL in each hotspot and found genes enriched for targets of small RNAs. Using fine mappings and mediation analysis, we identified candidate variants and genes for each distant eQTL of small RNA targets. Our results showed genetic variants in the gene eri-6 could underlie the expression variation of 10 genes. We found the genetic variant in the isoform eri-6[e] reduced the expression of eri-6[e] but elevated the expression of eri-6[a-d], which encodes the endogenous RNA interference factor ERI-6/7. Elevated levels of ERI-6/7 promote the biogenesis of endogenous ERI-6/7–dependent small interference RNAs (siRNAs) and likely reduce expression of targets, including the 10 genes above. The ERI-6/7–dependent siRNAs primarily target recently acquired, duplicated genes, and pseudogenes with likely viral origins. Stronger suppression of these targets could provide extra protection from overexpression of endogenous viral elements and future infections by viruses closely related to endogenous retroviruses. Our results reveal the diversity in RNA interference pathways among wild C. elegans strains and provide evidence of the role of small RNAs in C. elegans defense mechanisms.