Subterranean Fishes of the World

5609

2022

AIM 2022

16

Most of the genome-wide association studies for complex diseases in humans have mainly identified causative alleles while we know very few protective loci. We are using a comparative evolutionary approach, leveraging Astyanax mexicanus, to elucidate how an organism can evolve metabolic syndrome-like symptoms of hyperglycemia, obesity, and insulin resistance and yet not develop the associated ill-effects of inflammation, and glucose toxicity. As cis-regulatory changes are a major driver of such complex disorders, we aimed to elucidate the role of non-coding genome in the metabolic adaptation of cavefish and performed genome-wide mapping of cis-regulatory elements (CREs) in the livers of surface and cavefish populations. We find that many CREs differ in their chromatin status between surface fish and cavefish, while the two independently derived cave populations have evolved remarkably similar regulatory signatures. Importantly, we identified a large number of CREs that have acquired mutations and have lost or gained regulatory potential during the adaptation to the cave environment. Using in vitro and in vivo functional testing of the candidate cis-regulatory elements, we find that genetic changes within them cause quantitative expression differences. Analyses of one such mutated CRE inside hpdb, a tyrosine metabolism pathway gene, showed that deletion of a binding site for IRF2 repressor protein in cavefish is sufficient to drive increased gene expression. This suggests a potential adaptive role for the mutation, with a trade-off between the conversion of tyrosine to melanin and TCA cycle intermediates as a strategy to survive nutrient-deprived conditions. Our study opens interesting avenues for future research on identification of CRE and transcription factor networks that enable starvationresistance, fat accumulation, hyperglycemia, etc. that will be pursued in future using high throughput reporter assays in Astyanax liver-derived cell lines.

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