Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice
Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice
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DOI：
10.1242/jeb.243595
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发表时间：
2022-01-01
影响因子：
2.8
通讯作者：
Scott, Graham R.
中科院分区：
文献类型：
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作者：
Ivy, Catherine M.;Wearing, Oliver H.;Scott, Graham R.
生理系统通常具有涌现特性，但遗传变异对生理的影响通常是未知的，这对理解表型进化机制提出了重大挑战。我们调查了血红蛋白（Hb）的遗传变异是否有助于鹿鼠（Peromyscus maniculatus）的高海拔适应与呼吸控制的进化变化有关。我们建立了F-2高原和低地鹿鼠的种群间杂交，以测试混合遗传背景下α-和β-珠蛋白变体的表型关联。Hb基因型对Hb-O-2亲和力有预期的影响，这与缺氧时动脉氧饱和度的差异有关。然而，高海拔基因型也与呼吸表型，应有助于提高缺氧时的O-2摄取。具有高原α-珠蛋白的小鼠表现出更有效的呼吸模式，高原纯合子在吸入O-2的范围内呼吸更深但频率更低，这种差异与高海拔地区原生鹿鼠种群呼吸模式的进化变化相当。高原β-珠蛋白纯合子小鼠对缺氧的反应增强。球蛋白变异体与呼吸表型变异的关联不能通过急性操纵Hb-O-2亲和力来概括，因为用依法依维拉尔（一种急性降低Hb-O-2亲和力的合成药物）治疗对常氧或缺氧时的呼吸没有影响。因此，适应性变化，血红蛋白可能有意想不到的生理影响，除了典型的功能，这种蛋白质在循环O-2运输。
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 F-2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of alpha- and beta-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb-O-2 affinity that were associated with differences in arterial O-2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O-2 uptake in hypoxia. Mice with highland alpha-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O-2, 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 beta-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb-O-2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb-O-2 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 O-2 transport.