Metabolism without GLUT4, UCP1 and leptin: mRNA expression analysis in chicken.

When analysing gene expression of >20 tissues in mice, we discovered the phenomenon of “disallowed” genes (financially supported by FWO - G067212N). Last year, we started analysis of evolutionary conservation of “disallowed genes” by defining a core set of mRNA encoding genes that are commonly present in the genomes of humans, chickens, lizards and coelacanth, representing 4 major classes of vertebrate life. Taking human genes as reference and searching (on a gene per gene basis) for the most homologous gene in the other species, we observed to our surprise that the chicken genome does not contain approximately 10% of the core set of 14000 genes found in the three other classes. Incomplete chicken genome sequencing is an unlikely cause for this result as (a) the same set of genes is also absent in all other bird genomes that are publicly available today; (b) these genes are not randomly scattered, but grouped in synthenic blocks; (c) some of these genes encode among the most studied proteins in biology and medicine. Examples are GLUT4 (the key insulin-responsive glucose transporter, preventing diabetes), leptin (the key hormone that regulates fat stores, preventing obesity), and UCP1 (a key uncoupling protein that generates body heat). We are intrigued by this phenomenon and want to understand the molecular basis of successful bird life despite this massive gene loss including key regulators of metabolism. We hypothesize that a new balance of interacting genes was established before bird evolution (150-200 million yrs ago) in which the massive loss of genes was compensated by one or several mechanisms: (a) adapted new function of remaining genes(neofunctionalization); (b) altered tissue-expression of remaining bird genes; (c) local gene duplication events, creating new bird-specific genes. In this project we want to address this hypothesis (1) by measuring the mRNA expression profile of a large chicken tissue panel in healthy adults, including pancreatic islets and (2) by measuring the response of mRNA expression in major organs of energy homeostasis (e.g. liver, muscle, fat, brain, pancreatic islets) to exposure to cold temperature, fasting or high fat feeding. As a tool we use a new type of Affymetrix Chicken Gene Arrays (measuring >95% of annotated chicken genes). We anticipate that with the generated information we will gain new insight into balanced metabolism in the absence of genes that are crucial for  iabetes and obesity in humans. We hope that with this new insight we could learn something that might be useful for novel strategies to treat or prevent patients with chronic metabolic disease.