Epistasis Among Adaptive Mutations in Deer Mouse Hemoglobin
By Chandrasekhar Natarajan, N. Inoguchi, R. Weber, A. Fago, H. Moriyama, J. Storz. 2013
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Holding Your Breath Hemoglobin and myoglobin are widely responsible for oxygen transport and storage (see the Perspective by Rezende). The ability of diving mammals to obtain enough oxygen to support extended dives and foraging is largely dependent on muscle myoglobin (Mb) content. Mirceta et al. (p. 1303) found that in mammalian lineages with an aquatic or semiaquatic lifestyle, Mb net charge increases, which may represent an adaptation to inhibit self-association of Mb at high intracellular concentrations. Epistasis results from nonadditive genetic interactions and can affect phenotypic evolution. Natarajan et al. (p. 1324) found that epistatic interactions were able to explain the increased hemoglobin oxygen-binding affinity observed in deer mice populations at high altitude. In mammals, the offloading of oxygen from hemoglobin is facilitated by a reduction in the blood's pH, driven by metabolically produced CO2. However, in fish, a reduction in blood pH reduces oxygen carrying capacity of hemoglobin. Rummer et al. (p. 1327) implanted fiber optic oxygen sensors within the muscles of rainbow trout and found that elevated CO2 levels in the water led to acidosis and elevated oxygen tensions. Deer mice have discovered that mutations distant from the oxygen-binding site help them live at high altitude. [Also see Perspective by Rezende] Epistatic interactions between mutant sites in the same protein can exert a strong influence on pathways of molecular evolution. We performed protein engineering experiments that revealed pervasive epistasis among segregating amino acid variants that contribute to adaptive functional variation in deer mouse hemoglobin (Hb). Amino acid mutations increased or decreased Hb-O2 affinity depending on the allelic state of other sites. Structural analysis revealed that epistasis for Hb-O2 affinity and allosteric regulatory control is attributable to indirect interactions between structurally remote sites. The prevalence of sign epistasis for fitness-related biochemical phenotypes has important implications for the evolutionary dynamics of protein polymorphism in natural populations.
Subfields: Ecology, Genetics, Molecular Biology
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- Adaptation in protein fitness landscapes is facilitated by indirect paths (2016, background): “Although there are examples showing that protein fitness in vitro correlates with organismal fitness in vivo (Natarajan et al., 2013; Wu et al., 2012) , this relation may not be linear and is likely to be systemspecific due to the difference in selection pressures in vitro and in vivo (Pál et al., 2”