A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans

Hugo Zeberg,Michael Dannemann,Kristoffer Sahlholm,Kristin Tsuo,Tomislav Maricic,Victor Wiebe,Wulf Hevers,Hugh P.C Robinson,Janet Kelso,Svante Pääbo

doi:10.1016/j.cub.2020.06.045

Abstract

The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in ∼0.4% of present-day Britons, where they are associated with heightened pain sensitivity.

Highlights

Whereas most genetic differences between Neanderthals and modern humans that affect gene products occur singly in genes across the genome, genes that carry several such differences are of particular note
Each group independently accumulated genetic changes that became frequent or fixed. Late in their history, Neanderthals and Denisovans mixed with modern humans, which resulted in many genetic variants from Neanderthals and Denisovans being present in humans today [3, 4]
One such case is the gene SCN9A, which encodes the Nav1.7 protein, a voltage-gated sodium channel in which all Neanderthal genomes sequenced to date carry three amino acid substitutions relative to modern humans: M932L; V991L; and D1908G

Summary

Introduction

Whereas most genetic differences between Neanderthals and modern humans that affect gene products occur singly in genes across the genome, genes that carry several such differences are of particular note. One such case is the gene SCN9A, which encodes the Nav1.7 protein, a voltage-gated sodium channel in which all Neanderthal genomes sequenced to date carry three amino acid substitutions relative to modern humans: M932L; V991L; and D1908G. At these positions, extant monkeys and apes share the modern human residues. Loss-of-function mutations of SCN9A cause insensitivity to pain [8] and anosmi

Methods

Results

Conclusion