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

被引：22

作者：

Cagliani, R. ^{[1
]}

Guerini, F. R. ^{[2
]}

Fumagalli, M. ^{[1
]}

Riva, S. ^{[1
]}

Agliardi, C. ^{[2
]}

Galimberti, D. ^{[3
]}

Pozzoli, U. ^{[1
]}

Goris, A. ^{[4
]}

Dubois, B. ^{[4
]}

Fenoglio, C. ^{[3
]}

Forni, D. ^{[1
]}

Sanna, S. ^{[5
]}

Zara, I. ^{[6
]}

Pitzalis, M. ^{[7
]}

Zoledziewska, M. ^{[7
]}

Cucca, F. ^{[5
,7
]}

Marini, F. ^{[1
]}

Comi, G. P. ^{[3
]}

Scarpini, E. ^{[3
]}

Bresolin, N. ^{[1
,3
]}

Clerici, M. ^{[8
,9
]}

Sironi, M. ^{[1
]}

机构：

[1] Sci Inst IRCCS E Medea, Bosisio Parini, Lecco, Italy

[2] Don C Gnocchi Fdn ONLUS, IRCCS, Lab Mol Med & Biotechnol, Milan, Italy

[3] Univ Milan, Dino Ferrari Ctr, Dept Neurol Sci, Fdn Ca Granda IRCCS Osped Maggiore Policlin, Milan, Italy

[4] Katholieke Univ Leuven, Lab Neuroimmunol, Dept Neurosci, Louvain, Belgium

[5] CNR, Ist Ric Genet & Biomed, Cagliari, Italy

[6] CRS4, Cagliari, Italy

[7] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy

[8] Univ Milan, Chair Immunol, Dept Biomed Sci & Technol LITA Segrate, Milan, Italy

[9] Fdn Don C Gnocchi, IRCCS, Milan, Italy

来源：

MOLECULAR BIOLOGY AND EVOLUTION | 2012年 / 29卷 / 06期

关键词：

ZC3HAV1; trans-specific polymorphism; balancing selection; multiple sclerosis; LINKAGE DISEQUILIBRIUM; NUCLEOTIDE DIVERSITY; MOLECULAR EVOLUTION; STATISTICAL-METHOD; GENE FLOW; DISEASE; CHIMPANZEE; IDENTIFICATION; DIVERGENCE; INFERENCE;

D O I：

10.1093/molbev/mss002

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1599 / 1613

页数：15

共 93 条

[21] Distribution and intensity of constraint in mammalian genomic sequence [J].