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Discovery of candidate disease genes in ENU-induced mouse mutants by large-scale sequencing, including a splice-site mutation in nucleoredoxin.

PLoS genetics | Dec 17, 2009

An accurate and precisely annotated genome assembly is a fundamental requirement for functional genomic analysis. Here, the complete DNA sequence and gene annotation of mouse Chromosome 11 was used to test the efficacy of large-scale sequencing for mutation identification. We re-sequenced the 14,000 annotated exons and boundaries from over 900 genes in 41 recessive mutant mouse lines that were isolated in an N-ethyl-N-nitrosourea (ENU) mutation screen targeted to mouse Chromosome 11. Fifty-nine sequence variants were identified in 55 genes from 31 mutant lines. 39% of the lesions lie in coding sequences and create primarily missense mutations. The other 61% lie in noncoding regions, many of them in highly conserved sequences. A lesion in the perinatal lethal line l11Jus13 alters a consensus splice site of nucleoredoxin (Nxn), inserting 10 amino acids into the resulting protein. We conclude that point mutations can be accurately and sensitively recovered by large-scale sequencing, and that conserved noncoding regions should be included for disease mutation identification. Only seven of the candidate genes we report have been previously targeted by mutation in mice or rats, showing that despite ongoing efforts to functionally annotate genes in the mammalian genome, an enormous gap remains between phenotype and function. Our data show that the classical positional mapping approach of disease mutation identification can be extended to large target regions using high-throughput sequencing.

Pubmed ID: 20011118 RIS Download

Mesh terms: Animals | Chromosome Mapping | Ethylnitrosourea | Exons | Gene Expression Profiling | Genes, Lethal | Mice | Mice, Mutant Strains | Mutation | Nuclear Proteins | Oxidoreductases

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Ensembl

A collection of genome databases for vertebrates and other eukaryotic species with DNA and protein sequence search capabilities. The goal of Ensembl is to automatically annotate the genome, integrate this annotation with other available biological data and make the data publicly available via the web. The range of available data has also expanded to include comparative genomics, variation and regulatory data. Ensembl allows users to: upload and analyze data and save it to an Ensembl account; search for a DNA or protein sequence using BLAST or BLAT; fetch desired data from the public database, using the Perl API; download the databases via FTP in FASTA, MySQL and other formats; and mine Ensembl with BioMart and export sequences or tables in text, HTML, or Excel format. The DNA sequences and assemblies used in the Ensembl genebuild are provided by various projects around the world. Ensembl has entered into an agreement with UCSC and NCBI with regard to sequence identifiers in order to improve consistency between the data provided by different genome browsers. The site also links to the Ensembl blog with updates on new species and sequences as they are added to the database.

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Primer3

Tool used to design PCR primers from DNA sequence - often in high-throughput genomics applications. It does everything from mispriming libraries to sequence quality data to the generation of internal oligos.

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UW Genome Sciences

Welcome to the Department of Genome Sciences, which began in September 2001 by the fusion of the Departments of Genetics and Molecular Biotechnology. Our goal is to address leading edge questions in biology and medicine by developing and applying genetic, genomic and computational approaches that take advantage of genomic information now available for humans, model organisms and a host of other species. Our faculty study a broad range of topics, including the genetics of E. coli, yeast, C. elegans, Drosophila, and mouse; human and medical genetics; mathematical, statistical and computer methods for analyzing genomes, and theoretical and evolutionary genetics; and genome-wide studies by such approaches as sequencing, transcriptional and translational analysis, polymorphism detection and identification of protein interactions. Our chair, Dr. Robert Waterston, joined the department in January 2003. Our department includes both faculty with primary appointments in Genome Sciences, as well as adjuncts in other departments and Seattle institutions. Nine faculty are members of the National Academy of Sciences, including 2001 Nobel Prize winner Dr. Lee Hartwell, who conducted much of his groundbreaking work in the Department of Genetics. Five training faculty are Howard Hughes Medical Institute Investigators. Graduate research in the Department leads to a Ph.D. in Genome Sciences and students may also choose to participate in the Computational Molecular Biology or Molecular Medicine programs. Our department has around 55 - 60 graduate students at any given time and has moved into the new William H. Foege Building.

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Pompep

FTP site to access Schizosaccharomyces pombe protein data.

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TargetScan

Data analysis service that predicts biological targets of miRNAs by searching for the presence of conserved 8mer and 7mer sites that match the seed region of each miRNA. As an option, nonconserved sites are also predicted. Also identified are sites with mismatches in the seed region that are compensated by conserved 3' pairing. In mammals, predictions are ranked based on the predicted efficacy of targeting as calculated using the context+ scores of the sites. As an option, predictions are also ranked by their probability of conserved targeting (PCT). TargetScanHuman considers matches to annotated human UTRs and their orthologs, as defined by UCSC whole-genome alignments. Conserved targeting has also been detected within open reading frames (ORFs). All data and code are downloadable.

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RepeatMasker

A software tool that screens DNA sequences for interspersed repeats and low complexity DNA sequences. The output of the program is a detailed annotation of the repeats that are present in the query sequence as well as a modified version of the query sequence in which all the annotated repeats have been masked (default: replaced by Ns). Currently over 56% of human genomic sequence is identified and masked by the program. Sequence comparisons in RepeatMasker are performed by one of several popular search engines including nhmmer, cross_match, ABBlast/WUBlast, RMBlast and Decypher. RepeatMasker makes use of curated libraries of repeats and currently supports Dfam ( profile HMM library ) and RepBase ( consensus sequence library ).

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