A Trans-Specific Polymorphism in ZC3HAV1 Is Maintained by Long-Standing Balancing Selection and May Confer Susceptibility to Multiple Sclerosis | Zendy

Rachele Cagliani | Zendy; Franca Rosa Guerini | Zendy; Matteo Fumagalli | Zendy; Stefania Riva | Zendy; Cristina Agliardi | Zendy; Daniela Galimberti | Zendy; Uberto Pozzoli | Zendy; An Goris | Zendy; Bénédicte Dubois | Zendy; Chiara Fenoglio | Zendy; Diego Forni | Zendy; Serena Sanna | Zendy; Ilenia Zara | Zendy; Maristella Pitzalis | Zendy; Magdalena Żołędziewska | Zendy; Francesco Cucca | Zendy; Fédérico Marini | Zendy; Giacomo P. Comi | Zendy; Elio Scarpini | Zendy; Nereo Bresolin | Zendy; Mario Clerici | Zendy; Manuela Sironi | Zendy

Open Access

A Trans-Specific Polymorphism in ZC3HAV1 Is Maintained by Long-Standing Balancing Selection and May Confer Susceptibility to Multiple Sclerosis

Author(s) -

Rachele Cagliani,

Franca Rosa Guerini,

Matteo Fumagalli,

Stefania Riva,

Cristina Agliardi,

Daniela Galimberti,

Uberto Pozzoli,

An Goris,

Bénédicte Dubois,

Chiara Fenoglio,

Diego Forni,

Serena Sanna,

Ilenia Zara,

Maristella Pitzalis,

Magdalena Żołędziewska,

Francesco Cucca,

Fédérico Marini,

Giacomo P. Comi,

Elio Scarpini,

Nereo Bresolin,

Mario Clerici,

Manuela Sironi

Publication year - 2012

Publication title -

molecular biology and evolution

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 6.637

H-Index - 218

eISSN - 1537-1719

pISSN - 0737-4038

DOI - 10.1093/molbev/mss002

Subject(s) - biology , nonsynonymous substitution , 1000 genomes project , genetics , population , negative selection , haplotype , imputation (statistics) , evolutionary biology , genome , balancing selection , selection (genetic algorithm) , gene , single nucleotide polymorphism , genetic variation , allele , genotype , missing data , demography , machine learning , sociology , artificial intelligence , computer science

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.

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