title: Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data.
abstract: Genome and exome sequencing yield extensive catalogues of human genetic variation. However, pinpointing the few phenotypically causal variants among the many variants present in human genomes remains a major challenge, particularly for rare and complex traits wherein genetic information alone is often insufficient. Here, we review approaches to estimate the deleteriousness of single nucleotide variants (SNVs), which can be used to prioritize disease-causal variants. We describe recent advances in comparative and functional genomics that enable systematic annotation of both coding and non-coding variants. Application and optimization of these methods will be essential to find the genetic answers that sequencing promises to hide in plain sight.
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA. gcooper@ hudsonalpha.org
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cooper
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D019143:Evolution, Molecular; D056726:Genetic Association Studies / Q000379:methods; D008040:Genetic Linkage; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011487:Protein Conformation; D017422:Sequence Analysis, DNA