Evolution of purine metabolism

Gene duplication has long been accepted as playing a major role in evolution. Recently, it has been hypothesized that gene loss might also play an important role in evolution. While this hypothesis has not systematically been tested, it is becoming clear that gene loss has played a role in recent human evolution. One pathway that has been repeatedly modified by both gene duplication and gene loss is purine metabolism. The goal of this dissertation is to use purine metabolism as a model system to explore the biological significance of gene duplication and gene loss with respect to evolution and disease. Through characterization of the purine catabolic pathway in mammals we identified a novel genetic difference between placental mammals and marsupials/monotremes. We hypothesize that this genetic difference distinguishes purine catabolism between these lineages. By performing a more detailed characterization of the purine catabolic pathway in vertebrates we discovered an unexpected fate following loss of UOX in the bird/reptile lineage. The patterns of gene retention and gene loss allowed us to hypothesize a new model of gene loss by which a single gene loss event can have longterm, indirect consequences on the evolutionary potential of many genes in the genome. Mutations in HPRT1, a salvage enzyme of purine metabolism, cause Lesch-Nyhan disease in humans; however, the clinical phenotype has not been successfully recapitulated in a mouse model. In this work, we reconstruct the evolutionary history of the HPRT-gene family and hypothesize that the lack of a disease phenotype in mouse is due to the absence of an HPRT1 paralog, PRTFDC1, in this species. To this end, we have developed a more humanized mouse model carrying the human PRTFDC1 locus. In this dissertation we provide empirical evidence to support the theory of adaptive gene loss and highlight the importance of understanding the history of gene duplication and gene loss when modeling human disease.