RESUMO
As the sequencing of healthy and disease genomes becomes more commonplace, detailed annotation provides interpretation for individual variation responsible for normal and disease phenotypes. Current approaches focus on direct changes in protein coding genes, particularly nonsynonymous mutations that directly affect the gene product. However, most individual variation occurs outside of genes and, indeed, most markers generated from genome-wide association studies (GWAS) identify variants outside of coding segments. Identification of potential regulatory changes that perturb these sites will lead to a better localization of truly functional variants and interpretation of their effects. We have developed a novel approach and database, RegulomeDB, which guides interpretation of regulatory variants in the human genome. RegulomeDB includes high-throughput, experimental data sets from ENCODE and other sources, as well as computational predictions and manual annotations to identify putative regulatory potential and identify functional variants. These data sources are combined into a powerful tool that scores variants to help separate functional variants from a large pool and provides a small set of putative sites with testable hypotheses as to their function. We demonstrate the applicability of this tool to the annotation of noncoding variants from 69 full sequenced genomes as well as that of a personal genome, where thousands of functionally associated variants were identified. Moreover, we demonstrate a GWAS where the database is able to quickly identify the known associated functional variant and provide a hypothesis as to its function. Overall, we expect this approach and resource to be valuable for the annotation of human genome sequences.
Assuntos
Bases de Dados Genéticas , Variação Genética , Genoma Humano , Anotação de Sequência Molecular , Proteínas de Ligação a DNA/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Internet , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas Nucleares/genética , Fases de Leitura Aberta , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Proteína 3 Induzida por Fator de Necrose Tumoral alfaRESUMO
Here, we present PatMatch, an efficient, web-based pattern-matching program that enables searches for short nucleotide or peptide sequences such as cis-elements in nucleotide sequences or small domains and motifs in protein sequences. The program can be used to find matches to a user-specified sequence pattern that can be described using ambiguous sequence codes and a powerful and flexible pattern syntax based on regular expressions. A recent upgrade has improved performance and now supports both mismatches and wildcards in a single pattern. This enhancement has been achieved by replacing the previous searching algorithm, scan_for_matches [D'Souza et al. (1997), Trends in Genetics, 13, 497-498], with nondeterministic-reverse grep (NR-grep), a general pattern matching tool that allows for approximate string matching [Navarro (2001), Software Practice and Experience, 31, 1265-1312]. We have tailored NR-grep to be used for DNA and protein searches with PatMatch. The stand-alone version of the software can be adapted for use with any sequence dataset and is available for download at The Arabidopsis Information Resource (TAIR) at ftp://ftp.arabidopsis.org/home/tair/Software/Patmatch/. The PatMatch server is available on the web at http://www.arabidopsis.org/cgi-bin/patmatch/nph-patmatch.pl for searching Arabidopsis thaliana sequences.