Supplementary Material for: A Potential Role for Glucose Transporters in the Evolution of Human Brain Size

Differences in cognitive abilities and the relatively large brain are among the most striking differences between humans and their closest primate relatives. The energy trade-off hypothesis predicts that a major shift in energy allocation among tissues occurred during human origins in order to support the remarkable expansion of a metabolically expensive brain. However, the molecular basis of this adaptive scenario is unknown. Two glucose transporters <i>(SLC2A1</i> and <i>SLC2A4)</i> are promising candidates and present intriguing mutations in humans, resulting, respectively, in microcephaly and disruptions in whole-body glucose homeostasis. We compared <i>SLC2A1</i> and <i>SLC2A4</i> expression between humans, chimpanzees and macaques, and found compensatory and biologically significant expression changes on the human lineage within cerebral cortex and skeletal muscle, consistent with mediating an energy trade-off. We also show that these two genes are likely to have undergone adaptation and participated in the development and maintenance of a larger brain in the human lineage by modulating brain and skeletal muscle energy allocation. We found that these two genes show human-specific signatures of positive selection on known regulatory elements within their 5′-untranslated region, suggesting an adaptation of their regulation during human origins. This study represents the first case where adaptive, functional and genetic lines of evidence implicate specific genes in the evolution of human brain size.

认知能力差异与相对较大的脑容量，是人类与其近缘灵长类亲属之间最显著的差异之一。能量权衡假说（Energy Trade-off Hypothesis）预测，在人类起源过程中，为支撑代谢成本高昂的大脑的显著扩张，机体各组织的能量分配发生了重大转变。然而，这一适应性演化场景的分子基础仍未明确。两种葡萄糖转运蛋白（glucose transporters）SLC2A1与SLC2A4是极具潜力的候选基因，且在人类中存在引人关注的突变，二者分别会引发小头畸形（microcephaly）与全身葡萄糖稳态（glucose homeostasis）紊乱。我们比较了人类、黑猩猩与猕猴的SLC2A1和SLC2A4表达水平，发现人类谱系（human lineage）的大脑皮层（cerebral cortex）与骨骼肌（skeletal muscle）中存在具有生物学意义的补偿性表达变化，这与介导能量权衡的作用相符。我们还证实，这两个基因大概率经历了适应性演化，并通过调控大脑与骨骼肌的能量分配，参与了人类谱系更大容量大脑的发育与维持。我们发现，这两个基因在其5'非翻译区（5'-untranslated region）的已知调控元件上，呈现出人类特有的正选择（positive selection）特征，这表明它们的调控机制在人类起源过程中发生了适应性演化。本研究首次通过适应性演化、功能与遗传学多维度证据，将特定基因与人类脑容量的演化直接关联起来。