Miranda, J. J. | Search bioRxiv

bioRxiv2022

Epigenetic biomarkers of autoimmune risk and protective antioxidant signaling in methylmercury-exposed adults

I.BackgroundEpigenome-wide association studies (EWAS) are a highly promising approach that can inform precision environmental health. However, current EWAS are underpowered for biomarker detection and increasing sample sizes will require substantial resources. Therefore, alternative approaches for identifying candidate biomarkers through EWAS are critical for moving the field forward. ObjectivesTo provide proof-of-principle that maximizing exposure variance in EWAS by selecting participants from disproportionately exposed global populations enables effective candidate biomarker detection, even in small sample sizes. MethodsWe profiled genome-wide DNA methylation using Illumina Infinium MethylationEPIC BeadChip in whole blood from N=32 individuals from Madre de Dios, Peru with high methylmercury (MeHg) exposure due to artisanal and small-scale gold mining. We compared DNA methylation in N=16 individuals with high (>10 g/g) vs. N=16 individuals with low (<1 g/g) total hair mercury (a proxy for methylmercury exposure), matched on age and sex. ResultsWe identified nine differentially methylated CpG sites (FDR<0.05), including several with known links to MeHg toxicity. The most significantly different CpG site was in an intronic enhancer of the SLC5A7 gene, which encodes the L-type amino acid transporter 1 (LAT1) that facilitates MeHg transport into protein-rich tissue, including muscle and brain. Our Gene Ontology and transcription factor motif enrichment analyses identified differential methylation of genes involved in several outcomes with established links to MeHg, including immune response, neurotoxicity, and type 2 diabetes (T2D) risk. Last, we identified candidate epigenetic biomarkers of PUFA-mediated protection against MeHg toxicity. DiscussionHere, we show that a small EWAS on samples with high MeHg exposure variance can detect candidate differentially methylated CpGs and pathways of interest relevant to MeHg biology. Similar EWAS in global populations with known high exposure variance can be leveraged to develop targeted, custom sequencing panels and microarrays limited to replicated, validated biomarkers of a given exposure.

genomics↗

bioRxiv2018

Antagonistic pleiotropy is unexpectedly rare in new mutations

Pleiotropic effects of mutations may underlie diverse biological phenomena such as ageing and specialization. In particular, antagonistic pleiotropy (\"AP\": when a mutation has opposite fitness effects in different environments) generates tradeoffs, which may constrain adaptation. Models of adaptation typically assume that AP is common - especially among large-effect mutations - and that pleiotropic effect sizes are positively correlated. The rare empirical tests of these assumptions have largely focused on beneficial mutations observed under strong selection, whereas most mutations are actually deleterious or neutral, and are removed by selection. We quantified the incidence, nature and effect size of pleiotropy for carbon utilization across 80 single mutations in Escherichia coli that arose under mutation accumulation (i.e. weak selection). Although ~46% of the mutations were pleiotropic, only 11% showed AP, which is lower than expected given the distributions of fitness effects for each resource. In some environments, AP was more common in large-effect mutations (but not synergistic pleiotropy, SP); whereas pleiotropic effect sizes were positively correlated for SP (but not AP). Thus, AP is generally rare, is not consistently enriched in large-effect mutations, and often involves weakly deleterious antagonistic effects. Our unbiased quantification of mutational effects therefore suggests that antagonistic pleiotropy is unlikely to cause maladaptive tradeoffs.

evolutionary biology↗