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Dan A Landau,
Scott L Carter,
Petar Stojanov,
Aaron McKenna,
Kristen Stevenson,
Michael S Lawrence,
Carrie Sougnez,
Chip Stewart,
Andrey Sivachenko,
Lili Wang, [......],
Kristian Cibulskis,
Bethany Tesar, Stacey Gabriel,
Nir Hacohen,
Matthew Meyerson,
Eric S Lander,
Donna Neuberg,
Jennifer R Brown,
Gad Getz,
Catherine J Wu
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ABSTRACT: Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.
Cell 02/2013; 152(4):714-26. · 32.40 Impact Factor
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ABSTRACT: Detection of somatic point substitutions is a key step in characterizing the cancer genome. However, existing methods typically miss low-allelic-fraction mutations that occur in only a subset of the sequenced cells owing to either tumor heterogeneity or contamination by normal cells. Here we present MuTect, a method that applies a Bayesian classifier to detect somatic mutations with very low allele fractions, requiring only a few supporting reads, followed by carefully tuned filters that ensure high specificity. We also describe benchmarking approaches that use real, rather than simulated, sequencing data to evaluate the sensitivity and specificity as a function of sequencing depth, base quality and allelic fraction. Compared with other methods, MuTect has higher sensitivity with similar specificity, especially for mutations with allelic fractions as low as 0.1 and below, making MuTect particularly useful for studying cancer subclones and their evolution in standard exome and genome sequencing data.
Nature Biotechnology 02/2013; · 29.50 Impact Factor
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Andrew Kirby,
Andreas Gnirke,
David B Jaffe,
Veronika Barešová,
Nathalie Pochet,
Brendan Blumenstiel,
Chun Ye,
Daniel Aird,
Christine Stevens,
James T Robinson, [......],
Seth L Alper,
Kerstin Lindblad-Toh, Stacey Gabriel,
P Suzanne Hart,
Aviv Regev,
Chad Nusbaum,
Stanislav Kmoch,
Anthony J Bleyer,
Eric S Lander,
Mark J Daly
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ABSTRACT: Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (∼1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
Nature Genetics 02/2013; · 35.53 Impact Factor
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Lorena Travaglini,
Francesco Brancati,
Jennifer Silhavy,
Miriam Iannicelli,
Elizabeth Nickerson,
Nadia Elkhartoufi,
Eric Scott,
Emily Spencer, Stacey Gabriel,
Sophie Thomas, [......],
Hulya Kayserili,
Gonul Ogur,
Andrea Poretti,
Sabrina Signorini,
Graziella Uziel,
Maha S Zaki,
Colin Johnson,
Tania Attié-Bitach,
Joseph G Gleeson,
Enza Maria Valente
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ABSTRACT: Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.European Journal of Human Genetics advance online publication, 6 February 2013; doi:10.1038/ejhg.2012.305.
European journal of human genetics: EJHG 02/2013; · 3.56 Impact Factor
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Stacey Gabriel,
Christopher O'Donnell,
Esteban Gonzalez Burchard,
Rebecca K F Sze,
George Church,
Francine Gachupin,
Ellen Wright Clayton,
Leslie G Biesecker,
Joseph V Thakuria,
P Pearl O'Rourke, [......],
Laura M Beskow,
Wylie Burke,
Rebecca Fisher,
Gail P Jarvik,
Mona Puggal,
Stephanie M Fullerton,
Rick Kittles,
Sheri D Schully,
Jennifer R Leib,
Alan R Shuldiner
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Yujin Hoshida,
Augusto Villanueva,
Angelo Sangiovanni,
Manel Sole,
Chin Hur,
Karin L Andersson,
Raymond T Chung,
Joshua Gould,
Kensuke Kojima,
Supriya Gupta,
Bradley Taylor,
Andrew Crenshaw, Stacey Gabriel,
Beatriz Minguez,
Massimo Iavarone,
Scott L Friedman,
Massimo Colombo,
Josep M Llovet,
Todd R Golub
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ABSTRACT: BACKGROUND & AIMS:: Liver cirrhosis affects 1%-2% of population and is the major risk factor of hepatocellular carcinoma (HCC). Hepatitis C cirrhosis-related HCC is the most rapidly increasing cause of cancer death in the US. Non-invasive methods have been developed to identify patients with asymptomatic, early-stage cirrhosis, increasing the burden of HCC surveillance, but biomarkers are needed to identify patients with cirrhosis who are most in need of surveillance. We investigated whether a liver-derived 186-gene signature previously associated with outcomes of patients with HCC is prognostic for patients newly diagnosed with cirrhosis but without HCC. METHODS:: We performed gene expression profile analysis of formalin-fixed needle biopsies from the livers of 216 patients with hepatitis C-related early-stage (Child-Pugh class A) cirrhosis who were prospectively followed for a median of 10 years at an Italian center. We evaluated whether the 186-gene signature was associated with death, progression of cirrhosis, and development of HCC. RESULTS:: Fifty-five (25%), 101 (47%), and 60 (28%) patients were classified as having poor-, intermediate-, and good-prognosis signatures, respectively. In multivariable Cox regression modeling, the poor-prognosis signature was significantly associated with death ( P =.004), progression to advanced cirrhosis ( P <.001), and development of HCC ( P =. ). The 10-year rates of survival were 63%, 74%, and 85% and the annual incidences of HCC were 5.8%, 2.2%, and 1.5% for patients with poor-, intermediate-, and good-prognosis signatures, respectively. CONCLUSIONS:: A 186-gene signature used to predict outcomes of patients with HCC is also associated with outcomes of patients with hepatitis C-related early-stage cirrhosis. This signature might be used to identify patients with cirrhosis in most need of surveillance and strategies to prevent their development of HCC.
Gastroenterology 01/2013; · 11.68 Impact Factor
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Roel G W Verhaak,
Pablo Tamayo,
Ji-Yeon Yang,
Diana Hubbard,
Hailei Zhang,
Chad J Creighton,
Sian Fereday,
Michael Lawrence,
Scott L Carter,
Craig H Mermel, [......],
Anna Defazio,
Michael J Birrer,
Joe W Gray,
John N Weinstein,
David D Bowtell,
Ronny Drapkin,
Jill P Mesirov,
Gad Getz,
Douglas A Levine,
Matthew Meyerson
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ABSTRACT: Because of the high risk of recurrence in high-grade serous ovarian carcinoma (HGS-OvCa), the development of outcome predictors could be valuable for patient stratification. Using the catalog of The Cancer Genome Atlas (TCGA), we developed subtype and survival gene expression signatures, which, when combined, provide a prognostic model of HGS-OvCa classification, named "Classification of Ovarian Cancer" (CLOVAR). We validated CLOVAR on an independent dataset consisting of 879 HGS-OvCa expression profiles. The worst outcome group, accounting for 23% of all cases, was associated with a median survival of 23 months and a platinum resistance rate of 63%, versus a median survival of 46 months and platinum resistance rate of 23% in other cases. Associating the outcome prediction model with BRCA1/BRCA2 mutation status, residual disease after surgery, and disease stage further optimized outcome classification. Ovarian cancer is a disease in urgent need of more effective therapies. The spectrum of outcomes observed here and their association with CLOVAR signatures suggests variations in underlying tumor biology. Prospective validation of the CLOVAR model in the context of additional prognostic variables may provide a rationale for optimal combination of patient and treatment regimens.
The Journal of clinical investigation 12/2012; · 15.39 Impact Factor
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Joel T Haas,
Harland S Winter,
Elaine Lim,
Andrew Kirby,
Brendan Blumenstiel,
Matthew Defelice, Stacey Gabriel,
David Branski,
Carrie A Grueter,
Mauro S Toporovski,
Tobias C Walther,
Mark J Daly,
Robert V Farese
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ABSTRACT: Congenital diarrheal disorders (CDDs) are a collection of rare, heterogeneous enteropathies with early onset and often severe outcomes. Here, we report a family of Ashkenazi Jewish descent, with 2 out of 3 children affected by CDD. Both affected children presented 3 days after birth with severe, intractable diarrhea. One child died from complications at age 17 months. The second child showed marked improvement, with resolution of most symptoms at 10 to 12 months of age. Using exome sequencing, we identified a rare splice site mutation in the DGAT1 gene and found that both affected children were homozygous carriers. Molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced. The precise cause of diarrhea is unknown, but we speculate that it relates to abnormal fat absorption and buildup of DGAT substrates in the intestinal mucosa. Our results identify DGAT1 loss-of-function mutations as a rare cause of CDDs. These findings prompt concern for DGAT1 inhibition in humans, which is being assessed for treating metabolic and other diseases.
The Journal of clinical investigation 11/2012; · 15.39 Impact Factor
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ABSTRACT: Pacific Biosciences technology provides a fundamentally new data type that provides the potential to overcome some limitations of current next generation sequencing platforms by providing significantly longer reads, single molecule sequencing, low composition bias and an error profile that is orthogonal to other platforms. With these potential advantages in mind, we here evaluate the utility of the Pacific Biosciences RS platform for human medical amplicon resequencing projects.
We evaluated the Pacific Biosciences technology for SNP discovery in medical resequencing projects using the Genome Analysis Toolkit, observing high sensitivity and specificity for calling differences in amplicons containing known true or false SNPs. We assessed data quality: most errors were indels (~14%) with few apparent miscalls (~1%). In this work, we define a custom data processing pipeline for Pacific Biosciences data for human data analysis.
Critically, the error properties were largely free of the context-specific effects that affect other sequencing technologies. These data show excellent utility for follow-up validation and extension studies in human data and medical genetics projects, but can be extended to other organisms with a reference genome.
BMC Genomics 08/2012; 13:375. · 4.07 Impact Factor
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ABSTRACT: Dubowitz syndrome (DS) is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies. Over 140 cases have been reported, but the genetic basis is not understood.
We enrolled a multiplex consanguineous family from the United Arab Emirates with many of the key clinical features of DS as reported in previous series. The family was analyzed by whole exome sequencing. RNA splicing was evaluated with reverse-transcriptase PCR, immunostaining and western blotting was performed with specific antibodies, and site-specific cytosine-5-methylation was studied with bisulfite sequencing.
We identified a homozygous splice mutation in the NSUN2 gene, encoding a conserved RNA methyltransferase. The mutation abolished the canonical splice acceptor site of exon 6, leading to use of a cryptic splice donor within an AluY and subsequent mRNA instability. Patient cells lacked NSUN2 protein and there was resultant loss of site-specific 5-cytosine methylation of the tRNA(Asp GTC) at C47 and C48, known NSUN2 targets.
Our findings establish NSUN2 as the first causal gene with relationship to the DS spectrum phenotype. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentation in DS that can include chromosomal instability and immunological defects.
Journal of Medical Genetics 05/2012; 49(6):380-5. · 6.36 Impact Factor
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Lili Wang,
Michael S Lawrence,
Youzhong Wan,
Petar Stojanov,
Carrie Sougnez,
Kristen Stevenson,
Lillian Werner,
Andrey Sivachenko,
David S DeLuca,
Li Zhang, [......], Stacey Gabriel,
Nir Hacohen,
Robin Reed,
Matthew Meyerson,
Todd R Golub,
Eric S Lander,
Donna Neuberg,
Jennifer R Brown,
Gad Getz,
Catherine J Wu
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ABSTRACT: The somatic genetic basis of chronic lymphocytic leukemia, a common and clinically heterogeneous leukemia occurring in adults, remains poorly understood.
We obtained DNA samples from leukemia cells in 91 patients with chronic lymphocytic leukemia and performed massively parallel sequencing of 88 whole exomes and whole genomes, together with sequencing of matched germline DNA, to characterize the spectrum of somatic mutations in this disease.
Nine genes that are mutated at significant frequencies were identified, including four with established roles in chronic lymphocytic leukemia (TP53 in 15% of patients, ATM in 9%, MYD88 in 10%, and NOTCH1 in 4%) and five with unestablished roles (SF3B1, ZMYM3, MAPK1, FBXW7, and DDX3X). SF3B1, which functions at the catalytic core of the spliceosome, was the second most frequently mutated gene (with mutations occurring in 15% of patients). SF3B1 mutations occurred primarily in tumors with deletions in chromosome 11q, which are associated with a poor prognosis in patients with chronic lymphocytic leukemia. We further discovered that tumor samples with mutations in SF3B1 had alterations in pre-messenger RNA (mRNA) splicing.
Our study defines the landscape of somatic mutations in chronic lymphocytic leukemia and highlights pre-mRNA splicing as a critical cellular process contributing to chronic lymphocytic leukemia.
New England Journal of Medicine 12/2011; 365(26):2497-506. · 53.30 Impact Factor
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Manuel A Rivas,
Mélissa Beaudoin,
Agnes Gardet,
Christine Stevens,
Yashoda Sharma,
Clarence K Zhang,
Gabrielle Boucher,
Stephan Ripke,
David Ellinghaus,
Noel Burtt, [......],
David Altshuler, Stacey Gabriel,
Guillaume Lettre,
Andre Franke,
Mauro D'Amato,
Dermot P B McGovern,
Judy H Cho,
John D Rioux,
Ramnik J Xavier,
Mark J Daly
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ABSTRACT: More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 × 10(-16), odds ratio ≈ 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.
Nature Genetics 11/2011; 43(11):1066-73. · 35.53 Impact Factor
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Gabor T Marth,
Fuli Yu,
Amit R Indap,
Kiran Garimella,
Simon Gravel,
Wen Fung Leong,
Chris Tyler-Smith,
Matthew Bainbridge,
Tom Blackwell,
Xiangqun Zheng-Bradley, [......],
David Altshuler,
Carlos D Bustamante,
Andrew G Clark,
Mark Daly,
Mark DePristo,
Paul Flicek, Stacey Gabriel,
Elaine Mardis,
Aarno Palotie,
Richard Gibbs
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ABSTRACT: Rare coding variants constitute an important class of human genetic variation, but are underrepresented in current databases that are based on small population samples. Recent studies show that variants altering amino acid sequence and protein function are enriched at low variant allele frequency, 2 to 5%, but because of insufficient sample size it is not clear if the same trend holds for rare variants below 1% allele frequency.
The 1000 Genomes Exon Pilot Project has collected deep-coverage exon-capture data in roughly 1,000 human genes, for nearly 700 samples. Although medical whole-exome projects are currently afoot, this is still the deepest reported sampling of a large number of human genes with next-generation technologies. According to the goals of the 1000 Genomes Project, we created effective informatics pipelines to process and analyze the data, and discovered 12,758 exonic SNPs, 70% of them novel, and 74% below 1% allele frequency in the seven population samples we examined. Our analysis confirms that coding variants below 1% allele frequency show increased population-specificity and are enriched for functional variants.
This study represents a large step toward detecting and interpreting low frequency coding variation, clearly lays out technical steps for effective analysis of DNA capture data, and articulates functional and population properties of this important class of genetic variation.
Genome biology 09/2011; 12(9):R84. · 6.63 Impact Factor
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Adam J Bass,
Michael S Lawrence,
Lear E Brace,
Alex H Ramos,
Yotam Drier,
Kristian Cibulskis,
Carrie Sougnez,
Douglas Voet,
Gordon Saksena,
Andrey Sivachenko, [......],
Ronald A Depinho,
Lynda Chin,
Levi A Garraway,
Charles S Fuchs,
Jose Baselga,
Josep Tabernero, Stacey Gabriel,
Eric S Lander,
Gad Getz,
Matthew Meyerson
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ABSTRACT: Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma and have surveyed exons of protein-coding genes for mutations in 11 affected individuals. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin in colorectal carcinogenesis, the fusion lacks the TCF4 β-catenin-binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events.
Nature Genetics 09/2011; 43(10):964-8. · 35.53 Impact Factor
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Richard R. Fabsitz,
Amy L. McGuire,
Richard R. Sharp,
Mona Puggal,
Laura M. Beskow,
Leslie G. Biesecker,
Ebony Bookman,
Wylie Burke,
Esteban Gonzalez Burchard,
George Church, [......],
Jennifer R. Leib,
Christopher O'Donnell,
P. Pearl O'Rourke,
Laura Lyman Rodriguez,
Sheri D. Schully,
Alan R. Shuldiner,
Rebecca K.F. Sze,
Joseph V. Thakuria,
Susan M. Wolf,
Gregory L. Burke
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ABSTRACT: Tremendous controversy surrounds return of individual research results and incidental findings in genetic and genomic research on human participants. Researchers traditionally have not offered individual research results back to human participants. However, with increasing recognition of the potential health importance of those results (which may indeed be life-saving), scholars, researchers, and policy makers have begun considering under what circumstances results should be offered back to participants, what results would warrant this effort, and how it should be done. This article is a significant new consensus statement growing out of a workshop convened by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH). Thirty top researchers, scholars, and participants in the policy debate worked for over a year to reach agreement on 5 core recommendations. The group offers two recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of investigators' obligation to return genetic research results. The group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final recommendation urges investigators working with identifiable research participant communities to engage those communities on the return of aggregate and individual research results.
Vanderbilt University Law School, Public Law & Legal Theory Research Paper Series. 01/2011;
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Sheila Fisher,
Andrew Barry,
Justin Abreu,
Brian Minie,
Jillian Nolan,
Toni M Delorey,
Geneva Young,
Timothy J Fennell,
Alexander Allen,
Lauren Ambrogio, [......],
Ramy Shammas,
John Stalker,
Sean M Sykes,
Jon Thompson,
John Walsh,
Andrew Zimmer,
Zac Zwirko, Stacey Gabriel,
Robert Nicol,
Chad Nusbaum
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ABSTRACT: Genome targeting methods enable cost-effective capture of specific subsets of the genome for sequencing. We present here an automated, highly scalable method for carrying out the Solution Hybrid Selection capture approach that provides a dramatic increase in scale and throughput of sequence-ready libraries produced. Significant process improvements and a series of in-process quality control checkpoints are also added. These process improvements can also be used in a manual version of the protocol.
Genome biology 01/2011; 12(1):R1. · 6.63 Impact Factor
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Jessica Shea,
Vineeta Agarwala,
Anthony A Philippakis,
Jared Maguire,
Eric Banks,
Mark Depristo,
Brian Thomson,
Candace Guiducci,
Robert C Onofrio,
Sekar Kathiresan, Stacey Gabriel,
Noël P Burtt,
Mark J Daly,
Leif Groop,
David Altshuler
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ABSTRACT: Noncoding variants at human chromosome 9p21 near CDKN2A and CDKN2B are associated with type 2 diabetes, myocardial infarction, aneurysm, vertical cup disc ratio and at least five cancers. Here we compare approaches to more comprehensively assess genetic variation in the region. We carried out targeted sequencing at high coverage in 47 individuals and compared the results to pilot data from the 1000 Genomes Project. We imputed variants into type 2 diabetes and myocardial infarction cohorts directly from targeted sequencing, from a genotyped reference panel derived from sequencing and from 1000 Genomes Project low-coverage data. Polymorphisms with frequency >5% were captured well by all strategies. Imputation of intermediate-frequency polymorphisms required a higher density of tag SNPs in disease samples than is available on first-generation genome-wide association study (GWAS) arrays. Our association analyses identified more comprehensive sets of variants showing equivalent statistical association with type 2 diabetes or myocardial infarction, but did not identify stronger associations than the original GWAS signals.
Nature Genetics 01/2011; 43(8):801-5. · 35.53 Impact Factor
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Richard R Fabsitz,
Amy McGuire,
Richard R Sharp,
Mona Puggal,
Laura M Beskow,
Leslie G Biesecker,
Ebony Bookman,
Wylie Burke,
Esteban Gonzalez Burchard,
George Church, [......],
Jennifer R Leib,
Christopher O'Donnell,
P Pearl O'Rourke,
Laura Lyman Rodriguez,
Sheri D Schully,
Alan R Shuldiner,
Rebecca K F Sze,
Joseph V Thakuria,
Susan M Wolf,
Gregory L Burke
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ABSTRACT: In January 2009, the National Heart, Lung, and Blood Institute convened a 28-member multidisciplinary Working Group to update the recommendations of a 2004 National Heart, Lung, and Blood Institute Working Group focused on Guidelines to the Return of Genetic Research Results. Changes in the genetic and societal landscape over the intervening 5 years raise multiple questions and challenges. The group noted the complex issues arising from the fact that technological and bioinformatic progress has made it possible to obtain considerable information on individuals that would not have been possible a decade ago. Although unable to reach consensus on a number of issues, the working group produced 5 recommendations. The working group offers 2 recommendations addressing the criteria necessary to determine when genetic results should and may be returned to study participants, respectively. In addition, it suggests that a time limit be established to limit the duration of obligation of investigators to return genetic research results. The group recommends the creation of a central body, or bodies, to provide guidance on when genetic research results are associated with sufficient risk and have established clinical utility to justify their return to study participants. The final recommendation urges investigators to engage the broader community when dealing with identifiable communities to advise them on the return of aggregate and individual research results. Creation of an entity charged to provide guidance to institutional review boards, investigators, research institutions, and research sponsors would provide rigorous review of available data, promote standardization of study policies regarding return of genetic research results, and enable investigators and study participants to clarify and share expectations for the handling of this increasingly valuable information with appropriate respect for the rights and needs of participants.
Circulation Cardiovascular Genetics 12/2010; 3(6):574-80. · 6.11 Impact Factor
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ABSTRACT: Cancers are caused by the accumulation of genomic alterations. Therefore, analyses of cancer genome sequences and structures provide insights for understanding cancer biology, diagnosis and therapy. The application of second-generation DNA sequencing technologies (also known as next-generation sequencing) - through whole-genome, whole-exome and whole-transcriptome approaches - is allowing substantial advances in cancer genomics. These methods are facilitating an increase in the efficiency and resolution of detection of each of the principal types of somatic cancer genome alterations, including nucleotide substitutions, small insertions and deletions, copy number alterations, chromosomal rearrangements and microbial infections. This Review focuses on the methodological considerations for characterizing somatic genome alterations in cancer and the future prospects for these approaches.
Nature Reviews Genetics 10/2010; 11(10):685-96. · 38.08 Impact Factor
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Aaron McKenna,
Matthew Hanna,
Eric Banks,
Andrey Sivachenko,
Kristian Cibulskis,
Andrew Kernytsky,
Kiran Garimella,
David Altshuler, Stacey Gabriel,
Mark Daly,
Mark A DePristo
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ABSTRACT: Next-generation DNA sequencing (NGS) projects, such as the 1000 Genomes Project, are already revolutionizing our understanding of genetic variation among individuals. However, the massive data sets generated by NGS--the 1000 Genome pilot alone includes nearly five terabases--make writing feature-rich, efficient, and robust analysis tools difficult for even computationally sophisticated individuals. Indeed, many professionals are limited in the scope and the ease with which they can answer scientific questions by the complexity of accessing and manipulating the data produced by these machines. Here, we discuss our Genome Analysis Toolkit (GATK), a structured programming framework designed to ease the development of efficient and robust analysis tools for next-generation DNA sequencers using the functional programming philosophy of MapReduce. The GATK provides a small but rich set of data access patterns that encompass the majority of analysis tool needs. Separating specific analysis calculations from common data management infrastructure enables us to optimize the GATK framework for correctness, stability, and CPU and memory efficiency and to enable distributed and shared memory parallelization. We highlight the capabilities of the GATK by describing the implementation and application of robust, scale-tolerant tools like coverage calculators and single nucleotide polymorphism (SNP) calling. We conclude that the GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Genome Research 09/2010; 20(9):1297-303. · 13.61 Impact Factor
