19 posts · 5,608 views
Dan Koboldt blogs about human genetics, genomics, and DNA sequencing in the post-genome era.
Daniel Koboldt
19 posts
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- February 4, 2010
- 11:59 AM
- 102 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
- January 28, 2010
- 03:00 PM
- 105 views
Subtyping Glioblastoma via Genomic Analysis
by Daniel Koboldt in Massgenomics
A recent paper in Cancer Cell reveals the power of integrated genomic datasets for understanding cancer origins and treatment. Members of the TCGA Research Network identified and characterized four glioblastoma subtypes using gene expression, somatic mutation, and copy number data.
Genetic Characteristics of GBM Subtypes
Each subtype was classified by gene expression clustering, and showed specific patterns [...]... Read more »
Verhaak, R., Hoadley, K., Purdom, E., Wang, V., Qi, Y., Wilkerson, M., Miller, C., Ding, L., Golub, T., & Mesirov, J. (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. DOI: 10.1016/j.ccr.2009.12.020
- January 15, 2010
- 10:16 AM
- 176 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
- January 6, 2010
- 12:23 PM
- 144 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
- December 31, 2009
- 11:26 AM
- 202 views
Sanger Adds Two Cancer Genomes
by Daniel Koboldt in Massgenomics
This week in Nature, investigators from Wellcome Trust Sanger Institute published the fourth and fifth complete cancer genomes. Interestingly, both are cancers in which the primary mutagen is known: malignant melanoma (UV light) and small-cell lung cancer (tobacco smoke). This seems to be important, because when I looked at the number of validated somatic coding [...]... Read more »
Pleasance ED, Cheetham RK, Stephens PJ, McBride DJ, Humphray SJ, Greenman CD, Varela I, Lin ML, Ordóñez GR, Bignell GR.... (2009) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature. PMID: 20016485
Pleasance ED, Stephens PJ, O'Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C.... (2009) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. PMID: 20016488
- December 29, 2009
- 11:38 AM
- 192 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
- December 23, 2009
- 11:57 AM
- 200 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
- December 11, 2009
- 12:07 PM
- 187 views
Mapping Bias in Short Read Alignment
by Daniel Koboldt in Massgenomics
A recent paper in Bioinformatics investigates the effect of read-mapping biases on detecting allele-specific expression (ASE) from RNA-Seq data. The authors generated 16 million 36-bp cDNA reads in each of two HapMap individuals on the Illumina/Solexa platform. When evaluating known SNPs for evidence of ASE, they observed that heterozygous SNPs exhibited a mapping bias favoring [...]... Read more »
Degner JF, Marioni JC, Pai AA, Pickrell JK, Nkadori E, Gilad Y, & Pritchard JK. (2009) Effect of read-mapping biases on detecting allele-specific expression from RNA-sequencing data. Bioinformatics (Oxford, England), 25(24), 3207-12. PMID: 19808877
- November 23, 2009
- 01:51 PM
- 194 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
- November 17, 2009
- 12:31 PM
- 242 views
Major Setback in Fight Against Breast Cancer
by Daniel Koboldt in Massgenomics
On the front page of this morning’s USA Today, the headline reads “Report: Mammograms may not be needed until age 50.“ The story covers the recent findings of the U.S. Preventive Services Task Force (USPSTF), published this month in Annals of Internal Medicine. In it, the “independent panel of experts” makes some rather startling recommendations. [...]... Read more »
U.S. Preventive Services Task Force. (2009) Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal medicine, 151(10), 716-726. info:/
- October 9, 2009
- 12:43 PM
- 300 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
- September 24, 2009
- 12:00 PM
- 270 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
- August 19, 2009
- 01:01 PM
- 363 views
Genetics of Human Longevity
by Daniel Koboldt in Massgenomics
A new study in PLoS ONE resequenced candidate genes in a cohort of the “healthy oldest-old” - individuals aged 85 or older that are healthy and have never been diagnosed with cancer, cardiovascular disease, Alzheimer’s, pulmonary disease, or diabetes. The idea is that these robust old-timers harbor genetic variants that reduce susceptibility to, or even [...]... Read more »
Halaschek-Wiener, J., Amirabbasi-Beik, M., Monfared, N., Pieczyk, M., Sailer, C., Kollar, A., Thomas, R., Agalaridis, G., Yamada, S., Oliveira, L.... (2009) Genetic Variation in Healthy Oldest-Old. PLoS ONE, 4(8). DOI: 10.1371/journal.pone.0006641
- August 6, 2009
- 10:27 AM
- 346 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
- July 17, 2009
- 10:29 AM
- 453 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
- July 1, 2009
- 04:31 PM
- 527 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
- June 22, 2009
- 10:31 AM
- 583 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
- June 16, 2009
- 11:59 AM
- 472 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
- 550 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
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