PgmNr Z590: Cavefish evolution as a natural model for metabolic diseases.

Authors:
N. Rohner 1 ; A. C. Aspiras 2 ; C. J. Tabin 2


Institutes
1) Stowers Institute for Medical Research, Kansas City, MO; 2) Harvard Medical School, Boston, MA.


Abstract:

Understanding the genetic basis of adaptation has broad implications not only for a basic understanding of evolution, but also for human pathologies given that many human diseases are a consequence of mis-adaptation to modern societies. The emerging cavefish model system Astyanax mexicanus has become an important fish species to address adaptation to extreme environments due to its unique ecology and the availability of genetic tools (e.g. QTL mapping) and genomic resources. Despite 180 million years divergence to zebrafish, cavefish is currently the closest related sequenced fish species on Ensembl.

Cave environments are typically dark and as a consequence nutrient deprived. We have previously shown that cavefish acquired impressive adaptations such as hyperphagia (increased appetite), starvation resistance and altered feeding behaviors to cope with these harsh conditions. Here, we have focused on the fatty livers and symptoms reminiscent of diabetes these fish develop. Interestingly, we detected only very low insulin levels in cavefish (compared to surface or zebrafish) partially due to lower numbers of beta-insulin producing cells in the pancreas. In addition, cavefish display strong insulin resistance when administered with ectopic insulin. Despite the consequential elevated and highly fluctuating blood glucose levels, cavefish live long and healthy lives, probing the question whether they have acquired mechanisms allowing them to cope with extreme nutritional levels.

Taking advantage of the newly available genome of Astyanax mexicanus and tissue specific RNA-Seq data, we identified mutations in the insulin receptor of cavefish most likely responsible for the observed insulin resistant phenotype. Importantly, the same mutations were found in cases of Type-II diabetic patients in human populations. Our findings in independently derived cavefish populations suggest that cavefish are inherently insulin resistant, potentially as an additional strategy to acquire better starvation resistance. We are currently using genome editing to functionally test these and other candidate mutations in zebrafish and cavefish itself to study in detail the molecular mechanisms underlying the adaptation of cavefish to the extreme and nutrient poor environments, thereby providing potential new insights into human health.