Epistasis Among Adaptive Mutations in Deer Mouse Hemoglobin

Natarajan, Chandrasekhar; Inoguchi, Noriko; Weber, Roy E.; Fago, Angela; Moriyama, Hideaki; Storz, Jay F.

doi:10.1126/science.1236862

Cited by 181 publications

(206 citation statements)

References 41 publications

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“…of the stripped Hb). In conjunction with results from other recent studies (Clementi et al, 2003;Natarajan et al, 2013;Storz et al, 2009;Storz et al, 2010a;Storz et al, 2012;Weber, 1992), the data summarized in Table1 indicate that rodent Hbs are generally far less responsive to DPG than the Hbs of humans and many other mammals.…”

Section: Discussionsupporting

confidence: 73%

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Revsbech

Tufts

Projecto-Garcia

et al. 2013

Journal of Experimental Biology

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SUMMARYSemi-fossorial ground squirrels face challenges to respiratory gas transport associated with the chronic hypoxia and hypercapnia of underground burrows, and such challenges are compounded in species that are native to high altitude. During hibernation, such species must also contend with vicissitudes of blood gas concentrations and plasma pH caused by episodic breathing. Here, we report an analysis of hemoglobin (Hb) function in six species of marmotine ground squirrels with different altitudinal distributions. Regardless of their native altitude, all species have high Hb-O 2 affinities, mainly due to suppressed sensitivities to allosteric effectors [2,3-diphosphoglycerate (DPG) and chloride ions]. This suppressed anion sensitivity is surprising given that all canonical anion-binding sites are conserved. Two sciurid species, the golden-mantled and thirteen-lined ground squirrel, have Hb-O 2 affinities that are characterized by high pH sensitivity and low thermal sensitivity relative to the Hbs of humans and other mammals. The pronounced Bohr effect is surprising in light of highly unusual amino acid substitutions at the C-termini that are known to abolish the Bohr effect in human HbA. Taken together, the high O 2 affinity of sciurid Hbs suggests an enhanced capacity for pulmonary O 2 loading under hypoxic and hypercapnic conditions, while the large Bohr effect should help to ensure efficient O 2 unloading in tissue capillaries. In spite of the relatively low thermal sensitivities of the sciurid Hbs, our results indicate that the effect of hypothermia on Hb oxygenation is the main factor contributing to the increased blood-O 2 affinity in hibernating ground squirrels.

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Section: Discussionsupporting

confidence: 73%

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Revsbech

Tufts

Projecto-Garcia

et al. 2013

Journal of Experimental Biology

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“…In this case, enhancement of nGRE-binding ability in the GR lineage and the loss of nGRE-binding ability in the MR and AncSR3 lineages were critical for development of divergent DNA specificity. Both computational and directed evolution studies have implicated epistasis as a primary factor in molecular evolution (34,35), and studies of historical protein divergence have established a major role for epistasis in specific cases (28,(36)(37)(38)(39)(40)(41).…”

Section: Discussionmentioning

confidence: 99%

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Hudson

Kossmann

Vera

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Many genomes contain families of paralogs-proteins with divergent function that evolved from a common ancestral gene after a duplication event. To understand how paralogous transcription factors evolve divergent DNA specificities, we examined how the glucocorticoid receptor and its paralogs evolved to bind activating response elements [(+)GREs] and negative glucocorticoid response elements (nGREs). We show that binding to nGREs is a property of the glucocorticoid receptor (GR) DNA-binding domain (DBD) not shared by other members of the steroid receptor family. Using phylogenetic, structural, biochemical, and molecular dynamics techniques, we show that the ancestral DBD from which GR and its paralogs evolved was capable of binding both nGRE and (+)GRE sequences because of the ancestral DBD's ability to assume multiple DNA-bound conformations. Subsequent amino acid substitutions in duplicated daughter genes selectively restricted protein conformational space, causing this dual DNA-binding specificity to be selectively enhanced in the GR lineage and lost in all others. Key substitutions that determined the receptors' response elementbinding specificity were far from the proteins' DNA-binding interface and interacted epistatically to change the DBD's function through DNA-induced allosteric mechanisms. These amino acid substitutions subdivided both the conformational and functional space of the ancestral DBD among the present-day receptors, allowing a paralogous family of transcription factors to control disparate transcriptional programs despite high sequence identity.evolution | glucocorticoid | epistasis | steroid receptors

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“…the independent colonization of high-altitude environments by multiple species) complement insights derived from controlled laboratory experiments. For example, comparative studies have documented that high-altitude rodents often have higher Hb and/or blood O 2 affinities than their lowland relatives (Hall et al, 1936;Bullard et al, 1966;Ostojic et al, 2002;Storz, 2007;Storz et al, 2009Storz et al, , 2010aNatarajan et al, 2013Natarajan et al, , 2015aJensen et al, 2016), and these observations complement the results of experiments demonstrating that increases in blood-O 2 affinity enhance tissue O 2 delivery and measures of physiological performance in rodents subjected to environmental hypoxia (Eaton et al, 1974;Turek et al, 1978a,b;Chappell and Snyder, 1984). Such consilience of evidence from comparative and experimental studies can greatly strengthen conclusions about the adaptive significance of evolutionary changes in Hb-O 2 affinity.…”

Section: Insights From Comparative Studiesmentioning

confidence: 99%

Hemoglobin–oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend?

Storz

2016

Journal of Experimental Biology

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In air-breathing vertebrates at high altitude, fine-tuned adjustments in hemoglobin (Hb)-O 2 affinity provide an energetically efficient means of mitigating the effects of arterial hypoxemia. However, it is not always clear whether an increased or decreased Hb-O 2 affinity should be expected to improve tissue O 2 delivery under different degrees of hypoxia, due to the inherent trade-off between arterial O 2 loading and peripheral O 2 unloading. Theoretical results indicate that the optimal Hb-O 2 affinity varies as a non-linear function of environmental O 2 availability, and the threshold elevation at which an increased Hb-O 2 affinity becomes advantageous depends on the magnitude of diffusion limitation (the extent to which O 2 equilibration at the blood-gas interface is limited by the kinetics of O 2 exchange). This body of theory provides a framework for interpreting the possible adaptive significance of evolved changes in Hb-O 2 affinity in vertebrates that have colonized high-altitude environments. To evaluate the evidence for an empirical generalization and to test theoretical predictions, I synthesized comparative data in a phylogenetic framework to assess the strength of the relationship between Hb-O 2 affinity and native elevation in mammals and birds. Evidence for a general trend in mammals is equivocal, but there is a remarkably strong positive relationship between Hb-O 2 affinity and native elevation in birds. Evolved changes in Hb function in highaltitude birds provide one of the most compelling examples of convergent biochemical adaptation in vertebrates.

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Epistasis Among Adaptive Mutations in Deer Mouse Hemoglobin

Cited by 181 publications

References 41 publications

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Hemoglobin function and allosteric regulation in semi-fossorial rodents (family Sciuridae) with different altitudinal ranges

Distal substitutions drive divergent DNA specificity among paralogous transcription factors through subdivision of conformational space

Hemoglobin–oxygen affinity in high-altitude vertebrates: is there evidence for an adaptive trend?

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