Analysis of Stop-Gain and Frameshift Variants in Human Innate Immunity Genes

• DOI: 10.1371/journal.pcbi.1003757
• Publication Date: 2014-07-24T14:56:34Z
• Authors: Antonio Rausell; Pejman Mohammadi; Paul J. McLaren; Istvan Bartha; Ioannis Xenarios; Jacques Fellay; Amalio Telenti
• Keywords: Exome

Loss-of-function variants in innate immunity genes are associated with Mendelian disorders the form of primary immunodeficiencies. Recent resequencing projects report that stop-gains and frameshifts collectively prevalent humans could be responsible for some inter-individual variability immune response. Current computational approaches evaluating loss-of-function carrying these rely on gene-level characteristics such as evolutionary conservation functional redundancy across genome. However, represent a particular case because they more likely to under positive selection duplicated. To create ranking severity would applicable we evaluated 17,764 stop-gain 13,915 frameshift from NHLBI Exome Sequencing Project 1,000 Genomes Project. Sequence-based features loss domains, isoform-specific truncation nonsense-mediated decay were found correlate variant allele frequency validated gene expression data. We integrated Bayesian classification scheme benchmarked its use predicting pathogenic against Online Inheritance Man (OMIM) disease frameshifts. The was applied assessment 335 236 affecting 227 interferon-stimulated genes. sequence-based score ranks according their potential cause disease, complements existing gene-based pathogenicity scores. Specifically, improves measurement impairment, discriminates different given appears particularly useful analysis less conserved