Evolutionary analysis identifies an MX2 haplotype associated with natural resistance to HIV-1 infection
| Autor: | Francesco Mazzotta, Irma Saulle, Juan A. Pineda, Mario Clerici, Rachele Cagliani, Chiara Pontremoli, Antonio Rivero-Juárez, Salomè Valentina Ibba, Federica Gnudi, Giulia Filippi, Antonio Caruz, Stefania Riva, Manuela Sironi, Sergio Lo Caputo, Claudia Tresoldi, Sarah Yahyaei, Uberto Pozzoli, Mara Biasin, Diego Forni, Luca De Gioia, Daria Trabattoni |
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| Rok vydání: | 2014 |
| Předmět: |
Myxovirus Resistance Proteins
Population HIV Infections Simian White People Evolution Molecular Negative selection Asian People Genetics Coding region Humans Allele Selection Genetic education Molecular Biology Gene Ecology Evolution Behavior and Systematics Phylogeny Disease Resistance education.field_of_study Natural selection biology Models Genetic Haplotype Computational Biology Genetic Variation biology.organism_classification Haplotypes HIV-1 |
| Zdroj: | Molecular biology and evolution. 31(9) |
| ISSN: | 1537-1719 |
| Popis: | The protein product of the myxovirus resistance 2 (MX2) gene restricts HIV-1 and simian retroviruses. We demonstrate that MX2 evolved adaptively in mammals with distinct sites representing selection targets in distinct branches; selection mainly involved residues in loop 4, previously shown to carry antiviral determinants. Modeling data indicated that positively selected sites form a continuous surface on loop 4, which folds into two antiparallel α-helices protruding from the stalk domain. A population genetics-phylogenetics approach indicated that the coding region of MX2 mainly evolved under negative selection in the human lineage. Nonetheless, population genetic analyses demonstrated that natural selection operated on MX2 during the recent history of human populations: distinct selective events drove the frequency increase of two haplotypes in the populations of Asian and European ancestry. The Asian haplotype carries a susceptibility allele for melanoma; the European haplotype is tagged by rs2074560, an intronic variant. Analyses performed on three independent European cohorts of HIV-1-exposed seronegative individuals with different geographic origin and distinct exposure route showed that the ancestral (G) allele of rs2074560 protects from HIV-1 infection with a recessive effect (combined P = 1.55 × 10(-4)). The same allele is associated with lower in vitro HIV-1 replication and increases MX2 expression levels in response to IFN-α. Data herein exploit evolutionary information to identify a novel host determinant of HIV-1 infection susceptibility. |
| Databáze: | OpenAIRE |
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