Genetic Basis of Metabolic Evolution in the Cave Fish Astyanax Mexicanus

Abstract

Organisms evolve to thrive in new environments. In spite of the role metabolism plays in adaptation, the genetic basis for metabolic variation remains poorly understood. Here we use independently derived populations of Astyanax mexicanus, a Mexican tetra, to interrogate the genetic basis of extreme metabolic variation between surface and cave adapted populations. In the cave environment, food is much more scarce than in nutrient-rich rivers. Cave populations of Astyanax mexicanus rely on sporadic input of food from outside the cave. As a result, cave fish populations have evolved a suite of metabolic traits such as: starvation resistance, hyperphagia, hyperglycemia, and insulin resistance. We examined starvation resistance and hyperphagia in cave fish, finding that all cave populations had elevated triglycerides and reduced weight loss while fasting. Intriguingly, only a subset of the cave populations exhibited hyperphagia. Using a candidate gene approach, we identified a conserved coding mutation in melanocortin 4 receptor (mc4r), specific to hyperphagic populations. A comparison of signaling efficiency demonstrate that the cave allele had reduced maximal response and reduced basal activity relative to the surface allele in vitro. We further show that the cave allele contributes to hyperphagia and starvation resistance in vivo. We also investigated variation in blood glucose regulation among cave and surface populations. We observed a dysregulation in blood glucose homeostasis and insulin resistance in a subset of cave populations. Those populations were carrying a mutation in insulin receptor that leads to reduced ligand binding in vitro and contributes to elevated blood glucose. Surface/cave hybrids carrying the allele are heavier than non-carriers and zebrafish genetically engineered with the cave allele are heavier and insulin resistant. Humans with an identical mutation have a severe form of insulin resistance and reduced life span. However, cave fish populations with this mutation have a similar life span to surface counterparts and do not accumulate advanced glycation end products typically associated with the progression of diabetes-associated pathologies. Together, these studies provide new insight on how complex metabolic systems such blood glucose and weight regulation evolve and vary among populations.