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.
