The primary focus of my research is the genetic and mechanistic basis of adaptive phenotypic evolution. In my lab we address questions about biochemical adaptation by integrating evolutionary analyses of DNA sequence variation with mechanistic appraisals of protein function, and we address questions about physiological adaptation by integrating systems-level analyses of transcriptional regulatory circuits and genome-scale metabolic networks with experimental studies of whole-animal physiological performance. We use a highly interdisciplinary approach that integrates molecular population genetics, molecular evolution, comparative genomics, functional genomics, structural biology, protein biochemistry, and whole-animal physiology. Much of our current work involves experimental studies of functional genetic variation in high-altitude mammals and birds to identify mechanisms of hypoxia adaptation.
MECHANISMS OF ADAPTIVE PROTEIN EVOLUTION
Globin proteins as a model system
One of our main projects involves a systematic comparative study of hemoglobin adaptation to hypoxia in high-altitude vertebrates. This research is motivated by questions about the repeatability and predictability of molecular adaptation, and the roles of mutational pleiotropy and epistasis in shaping trajectories of protein evolution. Specifically, we are testing hypotheses about how pleiotropic trade-offs and epistatic interactions influence the selective accessibility of alternative mutational pathways during adaptive protein evolution. Our functional studies of native hemoglobins in mammals and birds are complemented by manipulative experiments that enable us to relate site-specific changes in hemoglobin structure to adaptive changes in blood biochemistry. Specifically, we are using a combinatorial protein engineering approach based on site-directed mutagenesis to measure the phenotypic effects of specific amino acid mutations in recombinant hemoglobins. This work involves collaborations with Chris Witt (University of New Mexico), Hideaki Moriyama (University of Nebraska), as well as Angela Fago and Roy E. Weber, both at Aarhus University, Denmark.
GENE DUPLICATION, GENOME DUPLICATION, AND EVOLUTIONARY INNOVATION
The globin gene superfamily as a model system
A second area of research is geared towards understanding the role of gene duplication and whole-genome duplication in the evolution of key physiological innovations. Gene duplication is thought to play an extremely important role in the evolution of novel protein and pathway functions. However, there is still much debate about the specific evolutionary mechanisms that are responsible for the initial retention and subsequent functional divergence of duplicated genes. The globin gene superfamily is an ideal model system for investigating these issues because it is one of the most intensively studied multigene families from the standpoint of molecular genetics and phylogenetic history. The globin gene families also provide an excellent example of the kind of physiological versatility that can be attained through functional and regulatory divergence of duplicated genes that encode different subunit polypeptides of the same multimeric protein. For example, in jawed vertebrates, different hemoglobin isoforms have been optimized for oxygen transport under the vastly different physiological conditions encountered during the embryonic, fetal, and adult stages of development. We are currently integrating comparative genomic analyses with experimental studies of protein function to investigate the evolution and functional diversification of the globin protein superfamily in the animal kingdom. This work involves a close collaboration with Federico G. Hoffmann (Mississippi State University) and Juan C. Opazo (Universidad Austral de Chile).
FUNCTIONAL GENOMICS AND SYSTEMS BIOLOGY OF HIGH-ALTITUDE ADAPTATION
A third area of research integrates experimental studies of whole-animal physiological performance with natural variation in genome-scale metabolic networks and transcriptional regulatory circuits. This work involves a systems-level analysis of physiological adaptation to hypoxic cold-stress in high-altitude deer mice and is motivated by questions about the mechanistic underpinnings of adaptive variation in organismal performance. The organismal phenotypes of interest are aerobic exercise capacity and thermogenic capacity under hypoxia. This work involves a close collaboration with Zac Cheviron (University of Illinois), Graham R. Scott (McMaster University, Canada), Grant B. McClelland (McMaster University, Canada), and Amina Qutub (Rice University).
NSF – “Causes of Parallel Molecular Evolution: Insights from Protein Engineering” (MCB-1517636, 2015-2018)
NSF – “Mechanisms and Evolution of Thermogenic Capacity in High-Altitude Deer Mice” (IOS-1354390, 2014-2017)
NIH – “Mutational Pleiotropy, Epistasis, and the Adaptive Evolution of Hemoglobin Function” (R01 HL087216, 2014-2019)
NIH – “Mechanisms of Hemoglobin Adaptation to Hypoxia in High Altitude Rodents” (R01 HL087216, 2008-2014)
NIH – National Heart, Lung, and Blood Institute, Diversity Supplement Award (2010-2012)
NIH – National Heart, Lung, and Blood Institute, ARRA Supplement Award (R01 HL087216-S1, 2009-2011)
NSF – “The Mechanistic Basis of Parallel Evolution: Functional Analysis of Hemoglobin Polymorphism in Andean Birds” (IOS-0949931, 2010-2013)
NSF – “A Test of Adaptive Divergence across Altitudinal Gradients: Population Genomics of Deer Mice” (DEB-0614342, 2006-2009)