title: Prioritizing genes for X-linked diseases using population exome data.
abstract: Many new disease genes can be identified through high-throughput sequencing. Yet, variant interpretation for the large amounts of genomic data remains a challenge given variation of uncertain significance and genes that lack disease annotation. As clinically significant disease genes may be subject to negative selection, we developed a prediction method that measures paucity of non-synonymous variation in the human population to infer gene-based pathogenicity. Integrating human exome data of over 6000 individuals from the NHLBI Exome Sequencing Project, we tested the utility of the prediction method based on the ratio of non-synonymous to synonymous substitution rates (dN/dS) on X-chromosome genes. A low dN/dS ratio characterized genes associated with childhood disease and outcome. Furthermore, we identify new candidates for diseases with early mortality and demonstrate intragenic localized patterns of variants that suggest pathogenic hotspots. Our results suggest that intrahuman substitution analysis is a valuable tool to help prioritize novel disease genes in sequence interpretation.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Ge
authors.affiliation: Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA Department of Dermatology, University of California San Francisco, San Francisco, CA 94143, USA and Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, USA shiehj2@humgen.ucsf.edu.
authors.forename: Joseph T C
authors.initials: JT
authors.lastname: Shieh
mesh_terms: D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D059472:Exome; D050172:Genes, X-Linked; D056726:Genetic Association Studies; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D012984:Software; D059467:Transcriptome