Melanocortin 4 receptor mutations contribute to the adaptation of cavefish to nutrient-poor conditions

A. C. Aspiras, N. Rohner, B. Martineau, R. L. Borowsky, C. J. Tabin

Research output: Contribution to journalArticle

Abstract

Despite recent advances in the understanding of morphological evolution, the genetic underpinnings of behavioral and physiological evolution remain largely unknown. Here, we study the metabolic changes that evolved in independently derived populations of the Mexican cavefish, Astyanax mexicanus. A hallmark of cave environments is scarcity of food. Cavefish populations rely almost entirely on sporadic food input from outside of the caves. To survive under these conditions, cavefish have evolved a range of adaptations, including starvation resistance and binge eating when food becomes available. The use of these adaptive strategies differs among independently derived cave populations. Although all cavefish populations tested lose weight more slowly than their surface conspecifics during restricted rations, only a subset of cavefish populations consume more food than their surface counterparts. A candidate gene-based screen led to the identification of coding mutations in conserved residues of the melanocortin 4 receptor (MC4R) gene, contributing to the insatiable appetite found in some populations of cavefish. Intriguingly, one of the mutated residues has been shown to be linked to obesity in humans. We demonstrate that the allele results in both reduced maximal response and reduced basal activity of the receptor in vitro. We further validate in vivo that the mutated allele contributes to elevated appetite, growth, and starvation resistance. The allele appears to be fixed in cave populations in which the overeating phenotype is present. The presence of the same allele in multiple caves appears to be due to selection from standing genetic variation present in surface populations.
Original languageUndefined
Pages (from-to)9668-73
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number31
DOIs
StatePublished - 2015

Keywords

  • Adaptation, Physiological/*genetics Aging/metabolism Amino Acid Sequence Animals Appetite *Caves Characidae/*genetics Conserved Sequence *Food Hyperphagia/physiopathology Liver/metabolism Male Molecular Sequence Data Mutation/*genetics Receptor, Melanocortin, Type 4/chemistry/*genetics

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Melanocortin 4 receptor mutations contribute to the adaptation of cavefish to nutrient-poor conditions. / Aspiras, A. C.; Rohner, N.; Martineau, B.; Borowsky, R. L.; Tabin, C. J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 31, 2015, p. 9668-73.

Research output: Contribution to journalArticle

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AU - Borowsky, R. L.

AU - Tabin, C. J.

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AB - Despite recent advances in the understanding of morphological evolution, the genetic underpinnings of behavioral and physiological evolution remain largely unknown. Here, we study the metabolic changes that evolved in independently derived populations of the Mexican cavefish, Astyanax mexicanus. A hallmark of cave environments is scarcity of food. Cavefish populations rely almost entirely on sporadic food input from outside of the caves. To survive under these conditions, cavefish have evolved a range of adaptations, including starvation resistance and binge eating when food becomes available. The use of these adaptive strategies differs among independently derived cave populations. Although all cavefish populations tested lose weight more slowly than their surface conspecifics during restricted rations, only a subset of cavefish populations consume more food than their surface counterparts. A candidate gene-based screen led to the identification of coding mutations in conserved residues of the melanocortin 4 receptor (MC4R) gene, contributing to the insatiable appetite found in some populations of cavefish. Intriguingly, one of the mutated residues has been shown to be linked to obesity in humans. We demonstrate that the allele results in both reduced maximal response and reduced basal activity of the receptor in vitro. We further validate in vivo that the mutated allele contributes to elevated appetite, growth, and starvation resistance. The allele appears to be fixed in cave populations in which the overeating phenotype is present. The presence of the same allele in multiple caves appears to be due to selection from standing genetic variation present in surface populations.

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