Physiological plasticity and the mechanisms of adaptation to hypoxia: exploiting natural variation in wild deer mice

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PROJECT SUMMARY The maintenance of O2 homeostasis is a critical component of human health. Its disruption, for example, contributes to the pathophysiology of many devastating diseases, including heart, lung, and cerebrovascular disease. In addition, pervasive reductions in environmental O2 availability at high altitudes pose a serious threat to the growing number of people worldwide that live above 2500 meters. For example, long-term exposure to high altitude hypoxia can lead to chronic conditions such as Chronic Mountain Sickness, as well as negative pregnancy outcomes, heart failure or even death. This is because under conditions of chronic environmental hypoxia, several physiological responses aimed at maintaining homeostasis under acute hypoxic conditions can lead to maladaptive remodeling of the pulmonary vasculature and increases in blood viscosity that can overburden the heart. In the Velotta lab, we study wild, high-altitude deer mice (Peromyscus maniculatus) as a model to understand the integrated evolutionary mechanisms that allow animals to overcome these challenges. Deer mice are a well-suited model: they are broadly distributed across > 4000 meters of elevation in North America, are easily captured in the wild and manipulated in the lab, are rich in physiological and genomic resources, and most importantly, have adapted over evolutionary time to the extreme conditions of high altitude. Over the next five years, my lab will dissect the genetic and molecular mechanisms by which natural selection has reshaped deer mouse physiology at high altitude. We will use quantitative genetics to identify, for the first time, the loci that underlie adaptive variation in physiological response to hypoxia, coupled with detailed RNA- sequencing and network-based transcriptomic approaches to identify the regulatory pathways that underlie such responses. Combining these approaches allows us to pinpoint the genetic architecture of evolved physiological change at high altitude. Finally, we will use our understanding of underlying genetic architecture to directly test for the form, direction, and strength of natural selection on physiological traits during adaptation to these extreme conditions. The large-scale and ambitious series of experiments outlined in this proposal will yield new insights into high-altitude biology and medicine and may lead to novel therapeutic targets for diseases in which the disruption of O2 homeostasis is central to their pathology.