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Abstract Anthropogenic stressors, such as pollutants, act as selective factors that can leave measurable changes in allele frequencies in the genome. Metals are of particular concern among pollutants, because of interference with vital biological pathways. We use the three‐spined stickleback as a model for adaptation to mercury pollution in natural populations. We collected sticklebacks from 21 locations in Flanders (Belgium), measured the accumulated levels of mercury in the skeletal muscle tissue, and genotyped the fish by sequencing (GBS). The spread of muscle mercury content across locations was considerable, ranging from 21.5 to 327 ng/g dry weight (DW). We then conducted a genome‐wide association study (GWAS) between 28,450 single nucleotide polymorphisms (SNPs) and the accumulated levels of mercury, using different approaches. Based on a linear mixed model analysis, the GWAS yielded multiple hits with a single top hit on Chromosome 4, with eight more SNPs suggestive of association. A second approach, a latent factor mixed model analysis, highlighted one single SNP on Chromosome 11. Finally, an outlier test identified one additional SNP on Chromosome 4 that appeared under selection. Out of all ten SNPs we identified as associated with mercury in muscle, three SNPs all located on Chromosome 4 and positioned within a 2.5 kb distance of an annotated gene. Based on these results and the genome coverage of our SNPs, we conclude that the selective effect of mercury pollution in Flanders causes a significant association with at least one locus on Chromosome 4 in three‐spined stickleback.

The circadian glucocorticoid-Krüppel-like factor 15-branched-chain amino acid (GC-KLF15-BCAA) signaling pathway is a key regulatory axis in muscle, whose imbalance has wide-reaching effects on metabolic homeostasis. Spinal muscular atrophy (SMA) is a neuromuscular disorder also characterized by intrinsic muscle pathologies, metabolic abnormalities and disrupted sleep patterns, which can influence or be influenced by circadian regulatory networks that control behavioral and metabolic rhythms. We therefore set out to investigate the contribution of the GC-KLF15-BCAA pathway in SMA pathophysiology of Taiwanese Smn−/−;SMN2 and Smn2B/− mouse models. We thus uncover substantial dysregulation of GC-KLF15-BCAA diurnal rhythmicity in serum, skeletal muscle and metabolic tissues of SMA mice. Importantly, modulating the components of the GC-KLF15-BCAA pathway via pharmacological (prednisolone), genetic (muscle-specific Klf15 overexpression) and dietary (BCAA supplementation) interventions significantly improves disease phenotypes in SMA mice. Our study highlights the GC-KLF15-BCAA pathway as a contributor to SMA pathogenesis and provides several treatment avenues to alleviate peripheral manifestations of the disease. The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders characterized by altered GC-KLF15-BCAA signaling. Keywords: Spinal muscular atrophy, KLF15, Glucocorticoids, Branched-chain amino acids, Metabolism, Therapy