TY - JOUR
T1 - Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice
AU - Ivy, Catherine M.
AU - Wearing, Oliver H.
AU - Natarajan, Chandrasekhar
AU - Schweizer, Rena M.
AU - Gutiérrez-Pinto, Natalia
AU - Velotta, Jonathan P.
AU - Campbell-Staton, Shane C.
AU - Petersen, Elin E.
AU - Fago, Angela
AU - Cheviron, Zachary A.
AU - Storz, Jay F.
AU - Scott, Graham R.
N1 - © 2022. Published by The Company of Biologists Ltd.
PY - 2022/1
Y1 - 2022/1
N2 - Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and β-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb-O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland β-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb-O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb-O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport.
AB - Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and β-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb-O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland β-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb-O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb-O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport.
KW - Evolutionary physiology
KW - Hypoxia acclimation
KW - Pulmonary ventilation
KW - Ventilatory acclimatization to hypoxia
UR - http://www.scopus.com/inward/record.url?scp=85123812513&partnerID=8YFLogxK
U2 - 10.1242/jeb.243595
DO - 10.1242/jeb.243595
M3 - Journal article
C2 - 34913467
AN - SCOPUS:85123812513
SN - 0022-0949
VL - 225
JO - Journal of Experimental Biology
JF - Journal of Experimental Biology
IS - 2
M1 - jeb243595
ER -