? Bitter-taste perception is a key mechanism of environmental response in humans. By allowing the individual to recognize potentially toxic compounds, bitter-taste perception allows control over their intake. Historically, the ability to perceive bitter compounds likely provided evolutionary advantages by allowing humans to avoid poisoning by plants, many of which use bitter toxins as a defense against herbivores. Many well-known bitter compounds such as quinine, nicotine, and caffeine, for example, are toxins produced naturally by plants. In modern populations, bitter-taste perception continues to be an important determinant of health through its effects on diet choice and other taste-related behaviors. For instance, significant associations are found between sensitivity to bitter compounds such as phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) and major health factors such as body mass index (DMI) and smoking tendencies. Given the importance of bitter-taste in human evolution and health, the applicant would like to know how evolutionary pressures have shaped patterns of variation in the genes underlying bitter-taste perception, and how these patterns of variation in turn shape bitter-taste phenotypes. This project will address patterns of genetic variation in human bitter-taste receptor genes to investigate the roles of demography and natural selection in shaping variation in these genes, and the contribution of variation in these genes to variance in bitter-taste phenotypes. First, 24 bitter-taste receptor genes will be resequenced in an ethnically diverse sample of 190 humans from 14 populations in Africa, Asia, Europe, and the Americas. Next, the data will be analyzed using population genetic methods to determine the roles of demography and natural selection in shaping patterns of diversity in each gene. Information about these effects will then be used to identify polymorphisms that have likely been maintained by balancing selection and local adaptation. Finally, variance component-based linkage analyses will be applied to the candidate polymorphisms and all polymorphisms to determine the relationship between variation in bitter-taste receptor genes and three phenotypes: PTC sensitivity, quinine sensitivity, and DMI. By applying a combined evolutionary and epidemiological approach, these analyses may shed new light on the relationship between genetic variation, environmental response, and human health. ? ? ?
