Date of Award
Doctor of Philosophy (PhD)
Joel D. Mainland
Many of the major milestones in understanding the olfactory system have arisen from research conducted in non-human animal models through the use of various genetic tools. While mammalian olfaction is largely conserved, there are several key differences in humans that suggest the necessity of studies directed at human olfaction. The human olfactory system has both genotypic variation and phenotypic variation, suggesting that, like in animal research, genetic tools are viable and vital for investigating human olfaction. We first address the basic questions of the human olfactory system, examining whether our assumptions based on animal olfaction are confirmed and attempting to identify mechanisms of the olfactory system that are not well-characterized in humans or other animals. We conducted whole exome sequencing on 52 individuals in ten families with congenital anosmia, an inherited disorder where individuals lack a sense of smell from birth. Through selection of rare, segregating, deleterious variants, we identified 215 genes that are associated with congenital anosmia. These genes are likely to play a role in olfaction, and can therefore serve as a resource for further investigation of the underlying mechanisms of basic human olfaction. We next investigated the relationship between olfactory receptors and odor perception in order to improve our understanding of how odor information is processed at the periphery. Here, we identified two novel associations: a variant in OR51B2 that increases intensity perception of a key component of body odor, and two-linked variants in OR4D6 that predict specific anosmia to the musk compound Galaxolide. Uncovering the relationship between odors and their specific receptors is the first step to understanding how the ~400 olfactory receptors work in combination to code for odor perception. These studies make advances towards a comprehensive understanding of how the human peripheral olfactory system functions and codes olfactory information into odor perception.
Kamarck, Marissa Lyn, "How Do Your Genes Smell? Applying Genetic Tools To Understand Olfactory Perception" (2022). Publicly Accessible Penn Dissertations. 4637.