31 posts · 9,846 views
Dan Koboldt blogs about human genetics, genomics, and DNA sequencing in the post-genome era.
Daniel Koboldt
31 posts
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- August 31, 2010
- 10:44 AM
- 28 views
Rapid Human Adaptation to High Altitudes
by Daniel Koboldt in Massgenomics
Two studies in the journal Science demonstrated that genes in the hypoxia-inducible factor (HIF) oxygen signaling pathway have undergone strong, recent positive selection in Tibetan highlanders. One study was a genome-wide scan using SNP arrays; the other a large-scale exome sequencing effort. The exome study was particularly interesting; using the Nimblegen 2.1M exon capture array [...]... Read more »
Storz, J. (2010) Genes for High Altitudes. Science, 329(5987), 40-41. DOI: 10.1126/science.1192481
Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB.... (2010) Genetic evidence for high-altitude adaptation in Tibet. Science (New York, N.Y.), 329(5987), 72-5. PMID: 20466884
Yi X, Liang Y, & Huerta-Sanchez E. (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science (New York, N.Y.), 329(5987), 75-8. PMID: 20595611
- August 25, 2010
- 12:06 PM
- 43 views
More Diagnosis by Whole Genome Resequencing
by Daniel Koboldt in Massgenomics
The cost of DNA sequencing continues to plummet, and while insurance companies might not be ready to get on board, another study has demonstrated how individual genome data can be clinically informative. Jonathan Rios and colleagues took on the case of an 11-month-old girl with severe hypercholesterolemia (1023 mg/dl) whose parents were unaffected, which suggested [...]... Read more »
Rios J, Stein E, Shendure J, Hobbs HH, & Cohen JC. (2010) Identification by Whole Genome Resequencing of Gene Defect Responsible for Severe Hypercholesterolemia. Human molecular genetics. PMID: 20719861
- August 11, 2010
- 07:09 PM
- 64 views
A Foundation for Next-Generation Analysis Tools
by Daniel Koboldt in Massgenomics
The emergence of next-generation sequencing has presented numerous significant challenges to the bioinformatics community. NGS instruments have given rise to a new generation of software tools for the alignment, assembly, management, and visualization of incredible amounts of data. New algorithms have also been developed to assess coverage, assess genomic copy number, call variants (SNPs/indels), and [...]... Read more »
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M.... (2010) The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome research. PMID: 20644199
- July 30, 2010
- 11:26 AM
- 85 views
Somatic Mutations in Four Human Cancers
by Daniel Koboldt in Massgenomics
In a letter to Nature this week, a group from Genentech presents an elegant analysis of 2,576 somatic mutations across 441 tumors comprised of breast, lung, ovarian, and prostate cancer types and subtypes. Using something called “mismatch repair detection” (MRD) technology, the authors surveyed 1,507 candidate genes spanning some 4 megabases of sequence, largely comprised [...]... Read more »
Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J.... (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature. PMID: 20668451
- June 30, 2010
- 04:26 PM
- 95 views
Not-so-whole Exome Sequencing
by Daniel Koboldt in Massgenomics
There is growing interest in applying next-generation sequencing to targeted regions of interest, particularly the “exome” - the set of coding exons in the human genome. A paper in Genome Biology from Matthew Bainbridge and colleagues at Baylor describes solution-phase exome capture and sequencing of a HapMap sample with just 3 GB of data. The [...]... Read more »
Bainbridge MN, Wang M, Burgess DL, Kovar C, Rodesch MJ, D'Ascenzo M, Kitzman J, Wu YQ, Newsham I, Richmond TA.... (2010) Whole exome capture in solution with 3Gbp of data. Genome biology, 11(6). PMID: 20565776
- June 2, 2010
- 01:05 PM
- 119 views
Mutation and Selection in a Lung Cancer Genome
by Daniel Koboldt in Massgenomics
A letter to Nature this week presents the whole-genome sequencing of a non-small-cell-lung cancer tumor. Over 500 validated mutations (530 SNVs and 43 structural variants) offer an unprecedented view of genetic variation and selection in solid tumors.
Using arrays of self-assembling DNA nanoballs (DNBs, i.e., the Complete Genomics platform), Lee et al sequenced a primary lung [...]... Read more »
Lee W, Jiang Z, Liu J, Haverty PM, Guan Y, Stinson J, Yue P, Zhang Y, Pant KP, Bhatt D.... (2010) The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature, 465(7297), 473-7. PMID: 20505728
- May 11, 2010
- 12:03 PM
- 143 views
A Formula for Dosing Humans with Rat Poison
by Daniel Koboldt in Massgenomics
In 1920, a mysterious epidemic broke out in the cattle populations of the United States and Canada. It was a severe disease of internal hemorrhaging that struck quickly and inexplicably; ranchers were soon distraught at the losses to their herds. Two years later, Frank Schofield connected the disease to sweet clover hay, which had been [...]... Read more »
Lenzini P, Wadelius M, Kimmel S, Anderson JL, Jorgensen AL, Pirmohamed M, Caldwell MD, Limdi N, Burmester JK, Dowd MB.... (2010) Integration of genetic, clinical, and INR data to refine warfarin dosing. Clinical pharmacology and therapeutics, 87(5), 572-8. PMID: 20375999
- May 4, 2010
- 11:52 AM
- 119 views
GWAS and the Genetics of Human Disease
by Daniel Koboldt in Massgenomics
An essay published last week in Cell dismissed the findings of genome-wide association studies (GWAS) and questioned their value to the study of human disease. In their article Genetic Heterogeneity in Human Disease, McLellan and King argue that because common diseases exhibit a high deegree of allelic, locus, and phenotypic heterogeneity, their causality “can almost [...]... Read more »
McClellan J, & King MC. (2010) Genetic heterogeneity in human disease. Cell, 141(2), 210-7. PMID: 20403315
- April 22, 2010
- 12:27 PM
- 220 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 15, 2010
- 10:06 AM
- 208 views
The Four Dimensions of a Breast Cancer Genome
by Daniel Koboldt in Massgenomics
Published today in the journal Nature is the whole-genome sequencing of a basal-like breast cancer tumor, metastasis, and xenograft. There’s also a News and Views article by Joe Gray of Lawrence Berkeley National Laboratory, as well as a news feature on large-scale cancer projects.
This study is a bit unlike our previous cancer genomes (AML1 and [...]... Read more »
Li Ding, Matthew J. Ellis, Shunqiang Li, David E. Larson, Ken Chen, John W. Wallis, Christopher C. Harris, Michael D. McLellan, Robert S. Fulton, Lucinda L. Fulton, Rachel M. Abbott, Jeremy Hoog, David J. Dooling, Daniel C. Koboldt, Heather Schmidt, Joell. (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature, 464(15), 999-1005. info:/10.1038/nature08989
- April 2, 2010
- 12:03 PM
- 180 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
- March 24, 2010
- 10:08 AM
- 169 views
Whole Genome Sequencing Diagnostics
by Daniel Koboldt in Massgenomics
This month in the New England Journal of Medicine, James Lupski and colleagues sequenced the complete genome of an individual with familial Charcot-Marie Tooth (CMT) disease. The “individual” is Lupski himself - he not only led the study, but served as patient zero. From conversations with some of my colleagues at Baylor, it’s clear that [...]... Read more »
Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L, Bainbridge M, Dinh H, Jing C, Wheeler DA.... (2010) Whole-Genome Sequencing in a Patient with Charcot-Marie-Tooth Neuropathy. The New England journal of medicine. PMID: 20220177
- February 4, 2010
- 11:59 AM
- 387 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
- 242 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
- 332 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
- 294 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
- 325 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
- 414 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
- 440 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
- 323 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
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