Thanks to the rapid and recent changes accompanying domestication, comparisons of wild and domestic life forms represent an ideal system for characterising the genetic basis of phenotypic diversity. Based on light coverage whole genome sequencing we recently compared patterns of genetic variation in dog and wolf to provide an initial understanding of the genetic basis of adaptations during dog domestication. We found that selection had targeted the entire pathway responsible for starch digestion and glucose absorption in the small intestine of dogs, indicating that a shift from a meat based to a starch rich diet constituted a crucial step during dog domestication. Combined with evidence that this change was accompanied by selection for mutations that also affected the ability to store glucose as fat, our findings argue that dogs underwent a general shift from a protein to a more carbohydrate based energy metabolism. Dog domestication may thus represent a unique and unexplored natural model for studying metabolism arguing that a detailed characterisation of the genetic basis of adaptations during dog domestication represents a novel perspective on the molecular components of insulin dependent carbohydrate and lipid metabolism. To benefit from this new perspective we describe a project that will use the characteristic genetic footprints left by recent selection to localise mutations that are likely to underlie metabolic adaptations in dog. Then we will use physiological experiments in genetically modified cell lines to test the effect of the indicated genes on insulin dependent metabolic processes with the dual objectives of characterising the genetic basis of dog domestication and identifying novel genes and mutations implicated in the control of lipid and carbohydrate metabolism. Given the important role of insulin resistance for the development of obesity associated diseases this project may open new avenues of research into pharmacological therapies aimed at cardiovascular disease and type 2 diabetes mellitus. To accomplish this work our specific aims are:
1. Collection and sequencing of a comprehensive sample of dogs and wolves.
2. Mapping of selection during dog domestication and filtering for candidate metabolic adaptations.
3. Functional validation of candidate carbohydrate and lipid metabolism genes using in vitro assays.