76 posts · 50,977 views
Dan Koboldt blogs about human genetics, genomics, and DNA sequencing in the post-genome era.
Daniel Koboldt
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- December 15, 2011
- 09:58 AM
- 1,540 views
Recurrent splicing mutations in MDS and leukemia
by Daniel Koboldt in Massgenomics
Myelodysplastic syndrome (MDS, also called preleukemia) is a blood disorder characterized by ineffective production of myeloid cells, or leukocytes. The disorderly and ineffective production of blood cells from stem cells in the bone marrow results in low blood counts, or cytopenias. As many of 30% of MDS cases progress to full-blown, chemotherapy-resistant secondary AML. This [...]... Read more »
Graubert TA, Shen D, Ding L, Okeyo-Owuor T, Lunn CL, Shao J, Krysiak K, Harris CC, Koboldt DC, Larson DE.... (2011) Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nature genetics. PMID: 22158538
Quesada V, Conde L, Villamor N, Ordóñez GR, Jares P, Bassaganyas L, Ramsay AJ, Beà S, Pinyol M, Martínez-Trillos A.... (2011) Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nature genetics. PMID: 22158541
- February 4, 2010
- 11:59 AM
- 1,512 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
- December 23, 2009
- 11:57 AM
- 1,490 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
- June 16, 2009
- 11:59 AM
- 1,253 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
- April 1, 2011
- 12:55 PM
- 1,193 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
- June 22, 2009
- 10:31 AM
- 1,142 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
- 1,139 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 5, 2009
- 05:32 PM
- 1,013 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
- 1,009 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 17, 2009
- 10:29 AM
- 975 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
- March 18, 2011
- 12:47 PM
- 958 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
- July 1, 2009
- 04:31 PM
- 911 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
- December 11, 2009
- 12:07 PM
- 909 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
- September 24, 2009
- 12:00 PM
- 879 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
- 875 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
- February 17, 2011
- 12:17 PM
- 864 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
- January 6, 2010
- 12:23 PM
- 858 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
- March 24, 2011
- 12:14 PM
- 837 views
Sequenced: A mouse model of leukemia
by Daniel Koboldt in Massgenomics
A study published yesterday in the Journal of Clinical Investigation reports the whole-genome sequencing of a mouse acute promyelocytic leukemia (APL) genome. This is a subtype of AML, characterized by the presence of a t(15;17) translocation that creates the PML-RARA fusion oncoprotein. In mice, you can induce expression of PML-RARA transgenically, and they’ll develop APL [...]... Read more »
Wartman, L., Larson, D., Xiang, Z., Ding, L., Chen, K., Lin, L., Cahan, P., Klco, J., Welch, J., Li, C.... (2011) Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression. Journal of Clinical Investigation. DOI: 10.1172/JCI45284
Rampal, R., & Levine, R. (2011) Finding a needle in a haystack: whole genome sequencing and mutation discovery in murine models. Journal of Clinical Investigation. DOI: 10.1172/JCI57200
- April 22, 2010
- 12:27 PM
- 820 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
- May 27, 2011
- 01:30 PM
- 810 views
A virus-associated liver cancer genome
by Daniel Koboldt in Massgenomics
In Nature Genetics last month, Yasushi Totoki and colleagues present the high-resolution characterization of hepatocellular carcinoma (HCC), the third most frequent cause of cancer-related death worldwide. The authors performed whole-genome sequencing (Illumina 2×50 bp) of the primary tumor (36x) and matched lymphocytes (28x) from a Japanese male with hepatitis C virus-positive liver cancer.
The epidemiology of [...]... Read more »
Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S, Tsutsumi S, Sonoda K, Totsuka H, Shirakihara T.... (2011) High-resolution characterization of a hepatocellular carcinoma genome. Nature genetics, 43(5), 464-9. PMID: 21499249
Wei X, Walia V, Lin JC, Teer JK, Prickett TD, Gartner J, Davis S, NISC Comparative Sequencing Program, Stemke-Hale K, Davies MA.... (2011) Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nature genetics, 43(5), 442-6. PMID: 21499247
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