Targeted capture and massively parallel sequencing of 12 human exomes. Export

@article{citeulike:5445743, abstract = {Genome-wide association studies suggest that common genetic variants explain only a modest fraction of heritable risk for common diseases, raising the question of whether rare variants account for a significant fraction of unexplained heritability. Although DNA sequencing costs have fallen markedly, they remain far from what is necessary for rare and novel variants to be routinely identified at a genome-wide scale in large cohorts. We have therefore sought to develop second-generation methods for targeted sequencing of all protein-coding regions ('exomes'), to reduce costs while enriching for discovery of highly penetrant variants. Here we report on the targeted capture and massively parallel sequencing of the exomes of 12 humans. These include eight HapMap individuals representing three populations, and four unrelated individuals with a rare dominantly inherited disorder, Freeman-Sheldon syndrome (FSS). We demonstrate the sensitive and specific identification of rare and common variants in over 300 megabases of coding sequence. Using FSS as a proof-of-concept, we show that candidate genes for Mendelian disorders can be identified by exome sequencing of a small number of unrelated, affected individuals. This strategy may be extendable to diseases with more complex genetics through larger sample sizes and appropriate weighting of non-synonymous variants by predicted functional impact.}, author = {Ng, Sarah B. and Turner, Emily H. and Robertson, Peggy D. and Flygare, Steven D. and Bigham, Abigail W. and Lee, Choli and Shaffer, Tristan and Wong, Michelle and Bhattacharjee, Arindam and Eichler, Evan E. and Bamshad, Michael and Nickerson, Deborah A. and Shendure, Jay}, citeulike-article-id = {5445743}, citeulike-linkout-0 = {http://dx.doi.org/10.1038/nature08250}, citeulike-linkout-1 = {http://dx.doi.org/10.1038/nature08250}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19684571}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19684571}, day = {10}, doi = {10.1038/nature08250}, issn = {1476-4687}, journal = {Nature}, keywords = {association, disease, expression, genome, human, sequencing, snps}, month = {September}, number = {7261}, pages = {272--276}, posted-at = {2009-09-09 20:28:18}, priority = {2}, publisher = {Nature Publishing Group}, title = {Targeted capture and massively parallel sequencing of 12 human exomes.}, url = {http://dx.doi.org/10.1038/nature08250}, volume = {461}, year = {2009} }

TY - JOUR ID - citeulike:5445743 L3 - citeulike-article-id:5445743 N2 - Genome-wide association studies suggest that common genetic variants explain only a modest fraction of heritable risk for common diseases, raising the question of whether rare variants account for a significant fraction of unexplained heritability. Although DNA sequencing costs have fallen markedly, they remain far from what is necessary for rare and novel variants to be routinely identified at a genome-wide scale in large cohorts. We have therefore sought to develop second-generation methods for targeted sequencing of all protein-coding regions ('exomes'), to reduce costs while enriching for discovery of highly penetrant variants. Here we report on the targeted capture and massively parallel sequencing of the exomes of 12 humans. These include eight HapMap individuals representing three populations, and four unrelated individuals with a rare dominantly inherited disorder, Freeman-Sheldon syndrome (FSS). We demonstrate the sensitive and specific identification of rare and common variants in over 300 megabases of coding sequence. Using FSS as a proof-of-concept, we show that candidate genes for Mendelian disorders can be identified by exome sequencing of a small number of unrelated, affected individuals. This strategy may be extendable to diseases with more complex genetics through larger sample sizes and appropriate weighting of non-synonymous variants by predicted functional impact. IS - 7261 JF - Nature SN - 1476-4687 EP - 276 TI - Targeted capture and massively parallel sequencing of 12 human exomes. PB - Nature Publishing Group VL - 461 SP - 272 KW - association KW - disease KW - expression KW - genome KW - human KW - sequencing KW - snps AU - Ng, Sarah AU - Turner, Emily AU - Robertson, Peggy AU - Flygare, Steven AU - Bigham, Abigail AU - Lee, Choli AU - Shaffer, Tristan AU - Wong, Michelle AU - Bhattacharjee, Arindam AU - Eichler, Evan AU - Bamshad, Michael AU - Nickerson, Deborah AU - Shendure, Jay PY - 2009/09/10/ UR - http://dx.doi.org/10.1038/nature08250 ER -