A trans-specific polymorphism in ZC3HAV1 is maintained by long-standing balancing selection and may confer susceptibility to multiple sclerosis

Abstract

The human ZC3HAV1 gene encodes an antiviral protein. The longest splicing isoform of ZC3HAV1 contains a C-terminal PARP-like domain, which has evolved under positive selection in primates. We analyzed the evolutionary history of this same domain in humans and in Pan troglodytes. We identified two variants that segregate in both humans and chimpanzees; one of them (rs3735007) does not occur at a hypermutable site and accounts for a nonsynonymous substitution (Thr851Ile). The probability that the two trans-specific polymorphisms have occurred independently in the two lineages was estimated to be low (P = 0.0054), suggesting that at least one of them has arisen before speciation and has been maintained by selection. Population genetic analyses in humans indicated that the region surrounding the shared variants displays strong evidences of long-standing balancing selection. Selection signatures were also observed in a chimpanzee population sample. Inspection of 1000 Genomes data confirmed these findings but indicated that search for selection signatures using low-coverage whole-genome data may need masking of repetitive sequences. A case-control study of more than 1,000 individuals from mainland Italy indicated that the Thr851Ile SNP is significantly associated with susceptibility to multiple sclerosis (MS) (odds ratio [OR] = 1.47, 95% confidence intervals [CI]: 1.08-1.99, P = 0.011). This finding was confirmed in a larger sample of 4,416 Sardinians cases/controls (OR = 1.18, 95% CI: 1.037-1.344, P = 0.011), but not in a population from Belgium. We provide one of the first instances of human/chimpanzee trans-specific coding variant located outside the major histocompatibility complex region. The selective pressure is likely to be virus driven; in modern populations, this variant associates with susceptibility to MS, possibly via the interaction with environmental factors.

Fig. 1.

Schematic diagram of the exon–intron structure of ZC3HAV1. Exons are indicated with the gray boxes. The two regions we resequenced are denoted by the hatched lines. The LD (r²) plot refers to CEU, and data were derived from HapMap. The two trans-specific SNPs are shown.

Fig. 2.

Nucleotide diversity and haplotype analysis in chimpanzee. (A) Plot of θ_W and π values for the 16 regions we analyzed (white circles) and for ZC3HAV1 region 2 (black). (B) Network analysis of region 2 in chimpanzee: the MRCA is indicated by the black circle; the position of the trans-specific variant is shown (arrow).

Fig. 3.

Median-joining network and GENETREE analysis of ZC3HAV1 haplotypes. (A) Median-joining network: each node represents a different haplotype, with the size of the circle proportional to frequency. Nucleotide differences between haplotypes are indicated on the branches of the network. Circles are color coded according to population (green: YRI, yellow: AA, blue: CEU, red: AS, and orange: SAI). The MRCA is also shown (black circle). The relative position of mutations along a branch is arbitrary. (B) GENETREE: mutations are represented as black dots and named for their physical position along the regions. The absolute frequency of each haplotype is also reported. Note that mutation numbering does not correspond to that reported in (A) (see Materials and Methods).