1. Rare missense variants in the human cytosolic antibody receptor preserve antiviral function.
- Author
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Zeng J, Slodkowicz G, and James LC
- Subjects
- Adenoviridae genetics, Antibodies, Viral genetics, Antibodies, Viral immunology, Binding Sites, Computational Biology methods, Conserved Sequence, Gene Expression, HEK293 Cells, Haplotypes, HeLa Cells, Healthy Volunteers, Humans, Models, Molecular, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Ribonucleoproteins genetics, Ribonucleoproteins immunology, Selection, Genetic, Adenoviridae chemistry, Antibodies, Viral chemistry, Mutation, Missense, Polymorphism, Genetic, Ribonucleoproteins chemistry
- Abstract
The genetic basis of most human disease cannot be explained by common variants. One solution to this 'missing heritability problem' may be rare missense variants, which are individually scarce but collectively abundant. However, the phenotypic impact of rare variants is under-appreciated as gene function is normally studied in the context of a single 'wild-type' sequence. Here, we explore the impact of naturally occurring missense variants in the human population on the cytosolic antibody receptor TRIM21, using volunteer cells with variant haplotypes, CRISPR gene editing and functional reconstitution. In combination with data from a panel of computational predictors, the results suggest that protein robustness and purifying selection ensure that function is remarkably well-maintained despite coding variation., Competing Interests: JZ, GS, LJ No competing interests declared, (© 2019, Zeng et al.) more...
- Published
- 2019
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