title: Analysis of stop-gain and frameshift variants in human innate immunity genes.
abstract: Loss-of-function variants in innate immunity genes are associated with Mendelian disorders in the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts are collectively prevalent in humans and could be responsible for some of the inter-individual variability in innate immune response. Current computational approaches evaluating loss-of-function in genes carrying these variants rely on gene-level characteristics such as evolutionary conservation and functional redundancy across the genome. However, innate immunity genes represent a particular case because they are more likely to be under positive selection and duplicated. To create a ranking of severity that would be applicable to innate immunity genes we evaluated 17,764 stop-gain and 13,915 frameshift variants from the NHLBI Exome Sequencing Project and 1,000 Genomes Project. Sequence-based features such as loss of functional domains, isoform-specific truncation and nonsense-mediated decay were found to correlate with variant allele frequency and validated with gene expression data. We integrated these features in a Bayesian classification scheme and benchmarked its use in predicting pathogenic variants against Online Mendelian Inheritance in Man (OMIM) disease stop-gains and frameshifts. The classification scheme was applied in the assessment of 335 stop-gains and 236 frameshifts affecting 227 interferon-stimulated genes. The sequence-based score ranks variants in innate immunity genes according to their potential to cause disease, and complements existing gene-based pathogenicity scores. Specifically, the sequence-based score improves measurement of functional gene impairment, discriminates across different variants in a given gene and appears particularly useful for analysis of less conserved genes.
authors: SIB Swiss Institute of Bioinformatics, Lausanne and Basel, Lausanne, Switzerland; Department of Laboratories, University Hospital of Lausanne, Lausanne, Switzerland; University of Lausanne, Lausanne, Switzerland; Vital-IT group, SIB Swiss Institute of Bioinformatics Lausanne, Lausanne, Switzerland.
authors: Antonio
authors: A
authors: Rausell
authors: SIB Swiss Institute of Bioinformatics, Lausanne and Basel, Lausanne, Switzerland; Computational Biology Group, ETH Zurich, Zurich, Switzerland.
authors: Pejman
authors: P
authors: Mohammadi
authors: SIB Swiss Institute of Bioinformatics, Lausanne and Basel, Lausanne, Switzerland; Department of Laboratories, University Hospital of Lausanne, Lausanne, Switzerland; School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors: Paul J
authors: PJ
authors: McLaren
authors: SIB Swiss Institute of Bioinformatics, Lausanne and Basel, Lausanne, Switzerland; Department of Laboratories, University Hospital of Lausanne, Lausanne, Switzerland; School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors: Istvan
authors: I
authors: Bartha
authors: SIB Swiss Institute of Bioinformatics, Lausanne and Basel, Lausanne, Switzerland; Vital-IT group, SIB Swiss Institute of Bioinformatics Lausanne, Lausanne, Switzerland; Swiss-Prot group, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors: Ioannis
authors: I
authors: Xenarios
authors: SIB Swiss Institute of Bioinformatics, Lausanne and Basel, Lausanne, Switzerland; School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors: Jacques
authors: J
authors: Fellay
authors: Department of Laboratories, University Hospital of Lausanne, Lausanne, Switzerland; University of Lausanne, Lausanne, Switzerland.
authors: Amalio
authors: A
authors: Telenti
mesh_terms: D001499:Bayes Theorem; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D014777:Virus Diseases / Q000276:immunology
chemical_list: D007372:Interferons