Historical Contingency in a Multigene Family Facilitates Adaptive Evolution of Toxin Resistance

Abstract

Novel adaptations must originate and function within an already established genome [1]. As a result, the ability of a species to adapt to new environmental challenges is predicted to be highly contingent on the evolutionary history of its lineage [2-6]. Despite a growing appreciation of the importance of historical contingency in the adaptive evolution of single proteins [7-11], we know surprisingly little about its role in shaping complex adaptations that require evolutionary change in multiple genes. One such adaptation, extreme resistance to tetrodotoxin (TTX), has arisen in several species of snakes through coevolutionary arms races with toxic amphibian prey, which select for TTX-resistant voltage-gated sodium channels (Nav) [12-16]. Here, we show that the relatively recent origins of extreme toxin resistance, which involve the skeletal muscle channel Nav1.4, were facilitated by ancient evolutionary changes in two other members of the same gene family. A substitution conferring TTX resistance to Nav1.7, a channel found in small peripheral neurons, arose in lizards ∼170 million years ago (mya) and was present in the common ancestor of all snakes. A second channel found in larger myelinated neurons, Nav1.6, subsequently evolved resistance in four different snake lineages beginning ∼38 mya. Extreme TTX resistance has evolved at least five times within the past 12 million years via changes in Nav1.4, but only within lineages that previously evolved resistant Nav1.6 and Nav1.7. Our results show that adaptive protein evolution may be contingent upon enabling substitutions elsewhere in the genome, in this case, in paralogs of the same gene family.

Convergent adaptation to dangerous prey proceeds through the same first‐step mutation in the garter snake Thamnophis sirtalis

“…In the standard genetic code, the adenine-guanine mutation found in both hotspots is the only single point mutation in a codon triplet capable of generating an isoleucine-valine amino acid change. Moreover, the I1561V change has never been found in eastern populations of T. sirtalis (Feldman et al 2009;Avila 2015), which are ancestral to the California and Northwest Coast clades in our SCN4A phylogeny, or in other TTX-resistant Thamnophis species (Feldman et al 2009(Feldman et al , 2012McGlothlin et al 2016). We surveyed a total of 111 individuals from 10 populations with low phenotypic resistance surrounding the hotspotsincluding five sites located between the two hotspots-and did not find evidence of the I1561V allele (Fig.…”

Convergent selection pressures drive the evolution of rhodopsin kinetics at high altitudes via nonparallel mechanisms

“…Our results also have implications for protein evolution, where molecular convergence in function underlain by nonparallel amino acid substitutions is an exciting new field of study (Manceau et al 2010;Natarajan et al 2016). Although epistasis, pleiotropy, and historical contingency may constrain protein functional convergence to be mediated by a limited number of parallel amino acid substitutions (Stern 2013;McGlothlin et al 2016;Storz 2016), nonparallelism can exist across a wide-range of proteins: GPCRs as demonstrated here in rhodopsin and previously in the melanocortin-1 receptor (Mc1r) receptor (Manceau et al 2010;Rosenblum et al 2010), sodium channels (Feldman et al 2012), metabolic antifreeze proteins (Chen et al 1997), as well as hemoglobin (Jessen et al 1991;Natarajan et al 2016). The overall prevalence of amino acid parallelism versus nonparallelism in protein functional convergence may depend on the tendency of a given protein function to be mediated by global versus local structural mechanisms.…”

“…Although epistasis, pleiotropy, and historical contingency may constrain protein functional convergence to be mediated by a limited number of parallel amino acid substitutions (Stern ; McGlothlin et al. ; Storz ), nonparallelism can exist across a wide‐range of proteins: GPCRs as demonstrated here in rhodopsin and previously in the melanocortin‐1 receptor (Mc1r) receptor (Manceau et al. ; Rosenblum et al.…”

Snake Genome Sequencing: Results and Future Prospects

“…Thus, the Eastern hog-nosed snake ( Heterodon platirhinos ) is resistant to the tetrodotoxin of Notophthalmus viridescens a newt on which it preys [72], and the garter snake Thamnophis sirtalis likewise shows resistance to the neurotoxic tetrodotoxin of newts in the genus Taricha [73]. Tetrodotoxin resistance in Thamnophis is due to modification of the amino acid sequence of tetrodotoxin targets: sodium ion channels on skeletal muscles (Na v 1.4) and peripheral neurons (Na v 1.6 and Na v 1.7; reviewed in Refs.…”

“…Tetrodotoxin resistance in Thamnophis is due to modification of the amino acid sequence of tetrodotoxin targets: sodium ion channels on skeletal muscles (Na v 1.4) and peripheral neurons (Na v 1.6 and Na v 1.7; reviewed in Refs. [73,74]). Analysis of snake genomic data and partial sequences, suggests that tetrodotoxin resistance in Thamnophis arose stepwise over a long period of evolutionary time, with the ancient modifications of the sodium channels in nerves providing the necessary conditions for evolution of resistance in skeletal muscle sodium-channels [73].…”