67 posts · 36,902 views
Dan Koboldt blogs about human genetics, genomics, and DNA sequencing in the post-genome era.
Daniel Koboldt
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- December 23, 2009
- 11:57 AM
- 1,329 views
Making the Leap: Maq to BWA
by Daniel Koboldt in Massgenomics
Like most curmudgeons I fought the change as stubbornly as I could. Leave Maq behind for something else? Never! Yet over the past few months I have come to realize that BWA, as it’s called, is not bad. At our genome center we still generate both Maq and BWA alignments for Illumina data; thanks to [...]... Read more »
Li, H., & Durbin, R. (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 25(14), 1754-1760. DOI: 10.1093/bioinformatics/btp324
- February 4, 2010
- 11:59 AM
- 1,173 views
VarScan 2 Released on SourceForge
by Daniel Koboldt in Massgenomics
Accurate variant detection in massively parallel sequencing data is a significant bioinformatics challenge. Not only do new sequencers offer unprecedented breadth (whole genome) and depth (30x or more), but they suffer coverage biases and error rates that make variant calling difficult. Last year, we published VarScan, our in-house algorithm for SNP and indel detection on [...]... Read more »
Koboldt DC, Chen K, Wylie T, Larson DE, McLellan MD, Mardis ER, Weinstock GM, Wilson RK, & Ding L. (2009) VarScan: variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics (Oxford, England), 25(17), 2283-5. PMID: 19542151
- June 22, 2009
- 10:31 AM
- 1,020 views
Variant Detection in Massively Parallel Sequencing
by Daniel Koboldt in Massgenomics
There is at last some evidence that I do real scientific work, and real scientific writing outside of Massgenomics. Online today at Bioinformatics is our publication of variant detection in massively parallel sequencing of individual and pooled samples. In it we present VarScan, the culmination of my work over the past two years to develop [...]... Read more »
Koboldt, D., Chen, K., Wylie, T., Larson, D., McLellan, M., Mardis, E., Weinstock, G., Wilson, R., & Ding, L. (2009) VarScan: Variant detection in massively parallel sequencing of individual and pooled samples. Bioinformatics. DOI: 10.1093/bioinformatics/btp373
- December 29, 2009
- 11:38 AM
- 971 views
SNP Discovery in NGS Data, Atlas-SNP2, and VarScan
by Daniel Koboldt in Massgenomics
A paper in this month’s Genome Research sheds light on predictors of sequencing error in next-generation sequencing. Using data from both 454 and Illumina platforms, Shen et al applied logistic regression models to identify sequence- and platform-related factors that contribute to substitution (SNP) errors.
The results, I think, offer new insight into the challenge of accurate [...]... Read more »
Shen Y, Wan Z, Coarfa C, Drabek R, Chen L, Ostrowski EA, Liu Y, Weinstock GM, Wheeler DA, Gibbs RA.... (2009) A SNP discovery method to assess variant allele probability from next-generation resequencing data. Genome research. PMID: 20019143
- June 16, 2009
- 11:59 AM
- 969 views
Inferring Function from Mutation in Cancer
by Daniel Koboldt in Massgenomics
As we continue to apply next-generation sequencing technologies to cancer genomes, we’re discovering hundreds of putative somatic mutations. Typically we run these through our annotation pipeline, which identifies variants affecting coding regions, splice sites, and evolutionarily conserved sequences. While a growing body of evidence suggests that much of the functional variation in humans lies outside [...]... Read more »
Lee, W., Yue, P., & Zhang, Z. (2009) Analytical methods for inferring functional effects of single base pair substitutions in human cancers. Human Genetics. DOI: 10.1007/s00439-009-0677-y
Ding, L., Getz, G., Wheeler, D., Mardis, E., McLellan, M., Cibulskis, K., Sougnez, C., Greulich, H., Muzny, D., Morgan, M.... (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature, 455(7216), 1069-1075. DOI: 10.1038/nature07423
Ley, T., Mardis, E., Ding, L., Fulton, B., McLellan, M., Chen, K., Dooling, D., Dunford-Shore, B., McGrath, S., Hickenbotham, M.... (2008) DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature, 456(7218), 66-72. DOI: 10.1038/nature07485
McLendon, R., Friedman, A., Bigner, D., Van Meir, E., Brat, D., M. Mastrogianakis, G., Olson, J., Mikkelsen, T., Lehman, N., Aldape, K.... (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature, 455(7216), 1061-1068. DOI: 10.1038/nature07385
- June 5, 2009
- 05:32 PM
- 899 views
Whole Genome Sequencing: How Many SNPs Remain?
by Daniel Koboldt in Massgenomics
This week’s publication of the genome of a Korean individual in Genome Research marks the fifth individual whole genome sequenced with massively parallel sequencing platforms. The fact that this was not a Nature paper speaks as loudly as anything. The window of time when single whole genome sequences merit high-profile publications is slowly closing.
It is [...]... Read more »
Wheeler, D., Srinivasan, M., Egholm, M., Shen, Y., Chen, L., McGuire, A., He, W., Chen, Y., Makhijani, V., Roth, G.... (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature, 452(7189), 872-876. DOI: 10.1038/nature06884
Ley, T., Mardis, E., Ding, L., Fulton, B., McLellan, M., Chen, K., Dooling, D., Dunford-Shore, B., McGrath, S., Hickenbotham, M.... (2008) DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature, 456(7218), 66-72. DOI: 10.1038/nature07485
Bentley, D., Balasubramanian, S., Swerdlow, H., Smith, G., Milton, J., Brown, C., Hall, K., Evers, D., Barnes, C., Bignell, H.... (2008) Accurate whole human genome sequencing using reversible terminator chemistry. Nature, 456(7218), 53-59. DOI: 10.1038/nature07517
Wang, J., Wang, W., Li, R., Li, Y., Tian, G., Goodman, L., Fan, W., Zhang, J., Li, J., Zhang, J.... (2008) The diploid genome sequence of an Asian individual. Nature, 456(7218), 60-65. DOI: 10.1038/nature07484
Ahn, S., Kim, T., Lee, S., Kim, D., Ghang, H., Kim, D., Kim, B., Kim, S., Kim, W., Kim, C.... (2009) The first Korean genome sequence and analysis: Full genome sequencing for a socio-ethnic group. Genome Research. DOI: 10.1101/gr.092197.109
- November 23, 2009
- 01:51 PM
- 872 views
Crossbow: NGS Informatics in the Cloud
by Daniel Koboldt in Massgenomics
Just online at Genome Biology is a new paper from the Steven Salzberg lab (UMD) on searching for SNPs with cloud computing. Using $85 of computing time rented from Amazon’s EC2, Langmead et al processed an entire human genome - 3.3 billion reads totaling 38x coverage - in three hours.
The “Cloud” Can Be Nebulous
Cloud computing [...]... Read more »
Ben Langmead, Michael C. Schatz, Jimmy Lin, Mihai Pop and Steven L. Salzberg. (2009) Searching for SNPs with cloud computing. Genome Biology, 10(R134). info:/doi:10.1186/gb-2009-10-11-r134
- July 1, 2009
- 04:31 PM
- 858 views
ABI SOLiD Joins the WGS Party
by Daniel Koboldt in Massgenomics
At last published in early access at Genome Research is the whole-genome sequencing of a Yoruban male on ABI SOLiD technology. A year ago, this might have merited a Nature or Science publication. That window seems to have closed for whole-genome sequencing of a single, undiseased individual. By my count, this is the sixth published [...]... Read more »
McKernan, K., Peckham, H., Costa, G., McLaughlin, S., Tsung, E., Fu, Y., Clouser, C., Dunkan, C., Ichikawa, J., Lee, C.... (2009) Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two base encoding. Genome Research. DOI: 10.1101/gr.091868.109
- July 17, 2009
- 10:29 AM
- 858 views
Integrating Genomic Analyses with Functional Validation in Cancer
by Daniel Koboldt in Massgenomics
Yesterday our group discussed the recent Nature paper from Lynda Chin’s lab that identified GOLPH3 as a “first-in-class” Golgi oncogene. The study began where most cancer genomics efforts end up: with the identification of a genomic region (5p13) that’s amplified in numerous solid tumours. The authors reasoned that the amplified region likely contains a gene [...]... Read more »
Scott, K., Kabbarah, O., Liang, M., Ivanova, E., Anagnostou, V., Wu, J., Dhakal, S., Wu, M., Chen, S., Feinberg, T.... (2009) GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer. Nature, 459(7250), 1085-1090. DOI: 10.1038/nature08109
- September 24, 2009
- 12:00 PM
- 769 views
Capture and Illumina Sequencing of Human Exomes
by Daniel Koboldt in Massgenomics
This month in Nature, a group from Jay Shendure’s lab reported perhaps the most ambitious targeted resequencing study to date - the whole exome sequences of 12 individuals.
Using an array-based hybridization capture method (2 microarrays, 10 g of input DNA), Ng et al selectively targeted CCDS regions totaling 26.6 Mb of sequence (~0.83% of the [...]... Read more »
Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE.... (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature, 461(7261), 272-6. PMID: 19684571
- February 25, 2011
- 01:19 AM
- 729 views
A Promising New Drug for Cystic Fibrosis
by Daniel Koboldt in Massgenomics
Today I got a call from a patient with cystic fibrosis, asking if I knew much about a specific mutation called 2184-del-A. It was a striking conversation, particularly because I tend to envision about infants and young children when I think about CF, and this woman was clearly an adult, a working professional, who had [...]... Read more »
Bompadre, S., Sohma, Y., Li, M., & Hwang, T. (2007) G551D and G1349D, Two CF-associated Mutations in the Signature Sequences of CFTR, Exhibit Distinct Gating Defects. The Journal of General Physiology, 129(4), 285-298. DOI: 10.1085/jgp.200609667
- January 6, 2010
- 12:23 PM
- 721 views
Finding Recurrent CNVs in Cancer
by Daniel Koboldt in Massgenomics
Copy number aberrations (CNAs) represent one of the most prevalent genetic alterations in cancer cells. There is considerable interest in finding CNAs that affect the same chromosomal region in multiple tumor samples. Recurrent CNA (RCNA) implies the presence of key cancer genes; on chromosome 7, for example, we often see amplification of the region containing [...]... Read more »
Zhang Q, Ding L, Larson DE, Koboldt DC, McLellan MD, Chen K, Shi X, Kraja A, Mardis ER, Wilson RK.... (2009) CMDS: a population-based method for identifying recurrent DNA copy number aberrations in cancer from high-resolution data. Bioinformatics (Oxford, England). PMID: 20031968
- February 17, 2011
- 12:17 PM
- 721 views
Chromothripsis and Cancer
by Daniel Koboldt in Massgenomics
The traditional cancer paradigm is one of progressive disease, in which cells gradually accumulate genomic rearrangements and point mutations over years (or decades), resulting in incremental progression through a series of increasingly malignant stages. New research has challenged that model. Using next-generation sequencing, Stephens et al have characterized a phenomenon in which tens to hundreds [...]... Read more »
Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA.... (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell, 144(1), 27-40. PMID: 21215367
- April 22, 2010
- 12:27 PM
- 709 views
Transcriptome Genetics with HapMap and RNA-Seq
by Daniel Koboldt in Massgenomics
Two papers in Nature this month leverage the power of second-generation sequencing technologies to investigate gene expression variation in human cell lines. By performing RNA-Seq in HapMap cell lines, the authors generated the most extensive gene expression data to date for these samples, and were able to use publicly available HapMap genotypes to associate expression [...]... Read more »
Pickrell JK, Marioni JC, Pai AA, Degner JF, Engelhardt BE, Nkadori E, Veyrieras JB, Stephens M, Gilad Y, & Pritchard JK. (2010) Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature, 464(7289), 768-72. PMID: 20220758
Montgomery SB, Sammeth M, Gutierrez-Arcelus M, Lach RP, Ingle C, Nisbett J, Guigo R, & Dermitzakis ET. (2010) Transcriptome genetics using second generation sequencing in a Caucasian population. Nature, 464(7289), 773-7. PMID: 20220756
- April 1, 2011
- 12:55 PM
- 706 views
The Cancer Methylome by MeDIP-Seq
by Daniel Koboldt in Massgenomics
Human cancers are driven by genetic and epigenetic changes to the genome of healthy cells. We often think about acquired mutations as the key drivers of tumor development and growth. Most studies empowered by next-gen sequencing have focused on identifying these changes. Yet aberrant DNA methylation - hypermethylation of tumor suppressor genes and hypomethylation of [...]... Read more »
Feber A, Wilson GA, Zhang L, Presneau N, Idowu B, Down TA, Rakyan VK, Noon LA, Lloyd AC, Stupka E.... (2011) Comparative methylome analysis of benign and malignant peripheral nerve sheath tumors. Genome research. PMID: 21324880
Down TA, Rakyan VK, Turner DJ, Flicek P, Li H, Kulesha E, Gräf S, Johnson N, Herrero J, Tomazou EM.... (2008) A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nature biotechnology, 26(7), 779-85. PMID: 18612301
- March 18, 2011
- 12:47 PM
- 689 views
Exome sequencing of human induced stem cells
by Daniel Koboldt in Massgenomics
Human induced pluripotent stem cells (hiPS cells) have incredible promise for therapeutic use. With genetically identical stem cell lines, it may become possible to replace cells or tissues that have been compromised by disease. Yet questions remain about the safety of hiPS cell lines. Does the induction of pluripotency alter the genome of the resulting [...]... Read more »
Gore A, Li Z, Fung HL, Young JE, Agarwal S, Antosiewicz-Bourget J, Canto I, Giorgetti A, Israel MA, Kiskinis E.... (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature, 471(7336), 63-7. PMID: 21368825
- October 9, 2009
- 12:43 PM
- 687 views
First Breast Cancer Genome in Nature
by Daniel Koboldt in Massgenomics
October is Breast Cancer Awareness Month, and the timing couldn’t be better. Our friends at the BC Cancer Agency published the whole genome sequencing of a breast cancer this week in a letter to Nature.
Using Illumina paired-end sequencing, Shah et al generated 141 Gbp of sequence to achieve 43x haploid coverage of a metastatic lobular [...]... Read more »
Shah, S., Morin, R., Khattra, J., Prentice, L., Pugh, T., Burleigh, A., Delaney, A., Gelmon, K., Guliany, R., Senz, J.... (2009) Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature, 461(7265), 809-813. DOI: 10.1038/nature08489
- August 6, 2009
- 10:27 AM
- 682 views
Second Cancer Genome in New England Journal
by Daniel Koboldt in Massgenomics
Today our group published the second cancer genome, AML2, in the New England Journal of Medicine. In this study, we sequenced the complete genomes of tumor cells and matched normal (skin) cells from a patient with cytogenetically normal de novo FAB M1 AML. This is an exciting publication for many reasons, the foremost of which [...]... Read more »
Mardis, E., Ding, L., Dooling, D., Larson, D., McLellan, M., Chen, K., Koboldt, D., Fulton, R., Delehaunty, K., McGrath, S.... (2009) Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia Genome. New England Journal of Medicine. DOI: 10.1056/NEJMoa0903840
- April 2, 2010
- 12:03 PM
- 655 views
Why We Sequence Cancer Genomes
by Daniel Koboldt in Massgenomics
A recent article on GenomeWeb profiling the XGen Congress meeting in San Diego, where researchers debated the question of whether sequencing cancer genomes has clinical relevance. In a roundtable discussion, University of Washington’s Larry Loeb argued that cancer is too heterogeneous for sequencing to uncover the therapeutically-relevant mutations. As an example, he pointed to AML1 [...]... Read more »
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP.... (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer cell, 17(1), 98-110. PMID: 20129251
- January 15, 2010
- 10:16 AM
- 653 views
Capture and Subassembly with Jay Shendure
by Daniel Koboldt in Massgenomics
Yesterday our 2010 Genetics Seminar Series kicked off with Jay Shendure (Univ. Washington) whose twelve-exome paper landed in Nature late last year. His talk covered three very different applications of next-generation sequencing: high-throughput mutational studies of core promoters, sub-assembly of Illumina reads to 454-length contigs, and exome capture to unravel Mendelian disorders.
Mutational Profiling
First, Dr. Shendure [...]... Read more »
Ng SB, Turner EH, Robertson PD, Flygare SD, Bigham AW, Lee C, Shaffer T, Wong M, Bhattacharjee A, Eichler EE.... (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature, 461(7261), 272-6. PMID: 19684571
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