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Sex linkage of the skeletal muscle sodium channel gene (SCN4A) explains apparent deviations from Hardy-Weinberg equilibrium of tetrodotoxin-resistance alleles in garter snakes (Thamnophis sirtalis).

ABSTRACT: The arms race between tetrodotoxin-bearing Pacific newts (Taricha) and their garter snake predators (Thamnophis) in western North America has become a classic example of coevolution, shedding light on predator-prey dynamics, the molecular basis of adaptation, and patterns of convergent evolution. Newts are defended by tetrodotoxin (TTX), a neurotoxin that binds to voltage-gated sodium channels (Na_v proteins), arresting electrical activity in nerves and muscles and paralyzing would-be predators. However, populations of the common garter snake (T. sirtalis) have overcome this defense, largely through polymorphism at the locus SCN4A, which renders the encoded protein (Na_v1.4) less vulnerable to TTX. Previous work suggests that SCN4A commonly shows extreme deviations from Hardy-Weinberg equilibrium (HWE) in these populations, which has been interpreted as the result of intense selection imposed by newts. Here we show that much of this apparent deviation can be attributed to sex linkage of SCN4A. Using genomic data and quantitative PCR, we show that SCN4A is on the Z chromosome in Thamnophis and other advanced snakes. Taking Z-linkage into account, we find that most apparent deviations from HWE can be explained by female hemizygosity rather than low heterozygosity. Sex linkage can affect mutation rates, selection, and drift, and our results suggest that Z-linkage of SCN4A may make significant contributions to the overall dynamics of the coevolutionary arms race between newts and snakes.

SUBMITTER: Gendreau KL

PROVIDER: S-EPMC7171075 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: Departure from Hardy Weinberg Equilibrium (HWE) may occur due to a variety of causes, including purifying selection, inbreeding, population substructure, copy number variation or genotyping error. We searched for specific characteristics of HWE-departure due to genotyping error. Methods: Genotypes of a random set of genetic variants were obtained from the Exome Aggregation Consortium (ExAC) database. Variants with <80% successful genotypes or with minor allele frequency (MAF) <1% were excluded. HWE-departure (d-HWE) was considered significant at p < 10E-05 and classified as d-HWE with loss of heterozygosity (LoH d-HWE) or d-HWE with excess heterozygosity (gain of heterozygosity: GoH d-HWE). Missing genotypes, variant type (single nucleotide polymorphism (SNP) vs. insertion/deletion); MAF, standard deviation (SD) of MAF across populations (MAF-SD) and copy number variation were evaluated for association with HWE-departure. Results: The study sample comprised 3,204 genotype distributions. HWE-departure was observed in 134 variants: LoH d-HWE in 41 (1.3%), GoH d-HWE in 93 (2.9%) variants. LoH d-HWE was more likely in variants located within deletion polymorphisms (p < 0.001) and in variants with higher MAF-SD (p = 0.0077). GoH d-HWE was associated with low genotyping rate, with variants of insertion/deletion type and with high MAF (all at p < 0.001). In a sub-sample of 2,196 variants with genotyping rate >98%, LoH d-HWE was found in 29 (1.3%) variants, but no GoH d-HWE was detected. The findings of the non-random distribution of HWE-violating SNPs along the chromosome, the association with common deletion polymorphisms and indel-variant type, and the finding of excess heterozygotes in genomic regions that are prone to cross-hybridization were confirmed in a large sample of short variants from the 1,000 Genomes Project. Conclusions: We differentiated between two types of HWE-departure. GoH d-HWE was suggestive for genotyping error. LoH d-HWE, on the contrary, pointed to natural variabilities such as population substructure or common deletion polymorphisms.

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Sex linkage of the skeletal muscle sodium channel gene (SCN4A) explains apparent deviations from Hardy-Weinberg equilibrium of tetrodotoxin-resistance alleles in garter snakes (Thamnophis sirtalis).

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