Abstract
Adrenergic α2C receptor (ADRA2C) is an inhibitory modulator of the sympathetic nervous system. Knockout mice for this gene show physiological and behavioural alterations that are associated with the fight-or-flight response. There is evidence of positive selection on the regulation of this gene during chicken domestication. Here, we find that the neuronal expression of ADRA2C is lower in human and chimpanzee than in other primates. On the basis of three-dimensional chromatin structure, we identified a cis-regulatory region whose DNA sequences have been significantly accelerated in human and chimpanzee. Active histone modification marks this region in rhesus macaque but not in human and chimpanzee; instead, repressive marks are enriched in various human brain samples. This region contains two neuron-restrictive silencer factor (NRSF) binding motifs, each of which harbours a polymorphism. Our genotyping and analysis of population genome data indicate that at both polymorphic sites, the derived allele has reached fixation in humans and chimpanzees but not in bonobos, whereas only the ancestral allele is present among macaques. Our CRISPR/Cas9 genome editing and reporter assays show that both derived nucleotides repress ADRA2C, most likely by increasing NRSF binding. In addition, we detected signatures of recent positive selection for lower neuronal ADRA2C expression in humans. Our findings indicate that there has been selective pressure for enhanced sympathetic nervous activity in the evolution of humans and chimpanzees.
Highlights
The sympathetic nervous system stimulates the fight-or-flight response of innervated target tissues by localized release of catecholamine neurotransmitters from the nerve terminals and by circulation of catecholamines released from the adrenal gland through the bloodstream
A strong selection signature in the genomes of domesticated chickens has been reported for this gene, suggesting that less aggression toward humans has been positively selected during chicken domestication
The adrenergic receptors are a class of G protein-coupled receptors that bind catecholamines, especially noradrenaline and adrenaline. α receptors have the subtypes α1 (Gq coupled receptor) and α2 (Gi coupled receptor). β receptors have the subtypes β1, β2 and β3. α2-adrenergic receptors are expressed on target tissues such as smooth muscles and at sympathetic nerve terminals, where they function as inhibitory presynaptic autoreceptors that modulate the release of neurotransmitters
Summary
The sympathetic nervous system stimulates the fight-or-flight response of innervated target tissues by localized release of catecholamine neurotransmitters from the nerve terminals and by circulation of catecholamines released from the adrenal gland through the bloodstream. Α2-adrenergic receptors are expressed on target tissues such as smooth muscles and at sympathetic nerve terminals, where they function as inhibitory presynaptic autoreceptors that modulate the release of neurotransmitters. The α2C subtype (ADRA2C) modulates neurotransmission at lower levels of nerve activity in brain cortex [1]. Multiple genes involved in the fight-or-flight response were identified as targets of selection during dog domestication [4]. One of the strongest selection signatures identified in the context of chicken domestication is located near ADRA2C [5]. A follow-up study suggests that the target of selection may be noncoding regulatory regions that are distant from the gene body [6]
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