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Dan Koboldt blogs about human genetics, genomics, and DNA sequencing in the post-genome era.

Daniel Koboldt
117 posts

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  • August 26, 2015
  • 08:00 AM
  • 23 views

Virtual Normals for Somatic Mutation Detection

by Daniel Koboldt in Massgenomics

In cancer genomics, we typically identify somatic alterations by sequencing DNA from both a tumor and a matched normal “control” sample from the same patient. The Cancer Genome Atlas and other large-scale efforts to characterize tumor genomes have typically used this approach, because it allows mutation callers (like VarScan 2) to distinguish between inherited variation and acquired (somatic) […]... Read more »

  • July 30, 2015
  • 08:00 AM
  • 132 views

New Insights into Human De Novo Mutations

by Daniel Koboldt in Massgenomics

De novo mutations — sequence variants that are present in a child but absent from both parents — are an important source of human genetic variation. I think it’s reasonable to say that most of the 3-4 million variants in any individual’s genome arose, once upon a time, as de novo mutations in his or her ancestors. […]... Read more »

Francioli LC, Polak PP, Koren A, Menelaou A, Chun S, Renkens I, Genome of the Netherlands Consortium, van Duijn CM, Swertz M, Wijmenga C.... (2015) Genome-wide patterns and properties of de novo mutations in humans. Nature genetics, 47(7), 822-6. PMID: 25985141  

  • July 16, 2015
  • 07:45 AM
  • 165 views

How to Succeed at Clinical Genome Sequencing

by Daniel Koboldt in Massgenomics

Whole-genome sequencing holds enormous potential to improve the diagnosis and treatment of human diseases. Although this approach is the only way to capture the complete spectrum of genetic variation, its application in clinical settings has been slow compared to more targeted strategies (i.e. panel and exome sequencing). Everyone talks about cost as the main contributing factor for […]... Read more »

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C.... (2015) Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nature genetics, 47(7), 717-26. PMID: 25985138  

  • June 19, 2015
  • 12:23 PM
  • 71 views

6 Realities of Genomic Research

by Daniel Koboldt in Massgenomics

The rise of next-generation sequencing has worked wonders for the field of genetics and genomics. It’s also generated a considerable amount of hype about the power of genome sequencing, particularly the possibility of individualized medicine based on genetic information. The rapid advances in technology — most recently, the Illumina X Ten system — have made […]... Read more »

Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL.... (2015) ClinGen--the Clinical Genome Resource. The New England journal of medicine, 372(23), 2235-42. PMID: 26014595  

  • June 3, 2015
  • 08:15 AM
  • 140 views

Clinical Sequencing Data Sharing Is Essential

by Daniel Koboldt in Massgenomics

The past few decades have seen rapid advances in our knowledge of genetic diseases, which affect an estimated 25 million Americans. These advances can be quantified in things like the growth of dbSNP (now contains about 90 million validated genetic variants) and the number of Mendelian disorders understood at the genetic level (over 5,000). Some of the […]... Read more »

Rehm HL, Berg JS, Brooks LD, Bustamante CD, Evans JP, Landrum MJ, Ledbetter DH, Maglott DR, Martin CL, Nussbaum RL.... (2015) ClinGen - The Clinical Genome Resource. The New England journal of medicine. PMID: 26014595  

  • May 14, 2015
  • 01:15 PM
  • 280 views

Mary-Claire King on Inherited Breast/Ovarian Cancer

by Daniel Koboldt in Massgenomics

It is a rare but delightful opportunity to learn about something from an acknowledged world expert. Such was the case last month when I heard Mary-Claire King give the Stanley J. Korsmeyer Memorial lecture, hands-down one of the best talks I’ve ever heard. She was a wonderful public speaker: funny, charming, and straight-shooting. Her topic, of […]... Read more »

Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, & King MC. (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science (New York, N.Y.), 250(4988), 1684-9. PMID: 2270482  

King MC. (2014) "The race" to clone BRCA1. Science (New York, N.Y.), 343(6178), 1462-5. PMID: 24675952  

  • April 20, 2015
  • 11:39 AM
  • 252 views

The Human Epigenome Roadmap

by Daniel Koboldt in Massgenomics

Aside from the occasional somatic mutation, the genome of every cell in an individual’s body is largely preserved. Yet different types of cells (and tissues, and organs) are incredibly diverse. The majority of that specialization is governed by epigenetic changes — histone modifications, DNA accessibility, and methylation — that influence when and how genes are expressed. […]... Read more »

Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J.... (2015) Integrative analysis of 111 reference human epigenomes. Nature, 518(7539), 317-30. PMID: 25693563  

  • April 6, 2015
  • 09:46 AM
  • 346 views

Rare Variants in Complex Disease: ABCA7 and Alzheimer’s

by Daniel Koboldt in Massgenomics

Although the cost of sequencing continues to fall precipitously (cue the NIH sequencing-versus-Moore’s-Law figure), it’s still expensive relative to high-throughput genotyping. Whole-genome sequencing on the X Ten costs around $2500 per sample by the time you account for basic analysis and data storage. This means that a well-powered genetic association study for complex disease (10,000 […]... Read more »

Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U.... (2015) Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease. Nature genetics. PMID: 25807283  

  • February 23, 2015
  • 12:48 PM
  • 301 views

Targeted Sequencing of GWAS Loci for Cleft Lip

by Daniel Koboldt in Massgenomics

In the last decade, genome-wide association studies (GWAS) enabled by cheap, high-throughput SNP genotyping have identified thousands of loci that influence disease susceptibility, quantitative traits, and other complex phenotypes. The genetic markers on high-density SNP arrays are carefully chosen to capture (or “tag”) most common haplotypes in human populations. Common SNPs tend to be more […]... Read more »

  • January 9, 2015
  • 08:00 AM
  • 603 views

Common disease genomics by large-scale sequencing

by Daniel Koboldt in Massgenomics

Understanding the genetic basis of common disease is an important goal for human genetics research. Nothing that we do is easy — the ~25% success rate of exome sequencing in monogenic (Mendelian) disorders is proof enough of that — but the challenges of complex disease genetics are considerable. Cardiovascular and metabolic diseases in particular arise […]... Read more »

Do R, Stitziel NO, Won H, Jørgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O.... (2014) Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature. PMID: 25487149  

  • November 21, 2014
  • 01:58 PM
  • 549 views

Genome, Evolution, and Domestication of the Cat

by Daniel Koboldt in Massgenomics

Even though most of my posts on MassGenomics concern human genetics and genomics, today I’d like to highlight a milestone in another species, one that many humans care fiercely about. This guy: Cat lovers, rejoice! This month in the Proceedings of the National Academy of Sciencs, Mike Montague, Wes Warren, and colleagues published the first complete […]... Read more »

Montague MJ, Li G, Gandolfi B, Khan R, Aken BL, Searle SM, Minx P, Hillier LW, Koboldt DC, Davis BW.... (2014) Comparative analysis of the domestic cat genome reveals genetic signatures underlying feline biology and domestication. Proceedings of the National Academy of Sciences of the United States of America. PMID: 25385592  

  • September 24, 2014
  • 11:42 AM
  • 526 views

Genetics "Experts" Surveyed on Returning Incidental Findings

by Daniel Koboldt in Massgenomics

In my last post, I wrote about the return of results from next-gen sequencing, specifically a recent paper in AJHG about secondary findings in ~6500 ESP exomes. Today we’ll delve into another paper in the same issue on the attitudes of genetics professionals on return of incidental findings from whole genome sequencing (WGS) and exome sequencing […]... Read more »

  • September 10, 2014
  • 08:00 AM
  • 465 views

Return of Results from Next-gen Sequencing

by Daniel Koboldt in Massgenomics

The rapid adoption of next-gen exome and genome sequencing for clinical use (i.e. with patient DNA) raises some difficult questions about the return of results to patients and their families. In contrast to traditional genetic testing, which usually checks for variants in specific genes, high-throughput sequencing has the potential to reveal a number of secondary […]... Read more »

  • May 23, 2014
  • 12:18 PM
  • 318 views

Promoters and Enhancers in the Human Genome

by Daniel Koboldt in Massgenomics

A recent issue of Nature featured two articles from the FANTOM5 project, an effort to systematically study gene expression and regulation by performingg capped analysis of gene expression (CAGE) across a diversity of cell types. FANTOM5 has generated single molecule CAGE profiles for 574 primary human cell samples, each sequenced to a median depth of […]... Read more »

FANTOM Consortium and the RIKEN PMI and CLST (DGT). (2014) A promoter-level mammalian expression atlas. Nature, 507(7493), 462-70. PMID: 24670764  

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, Chen Y, Zhao X, Schmidl C, Suzuki T.... (2014) An atlas of active enhancers across human cell types and tissues. Nature, 507(7493), 455-61. PMID: 24670763  

  • May 6, 2014
  • 11:12 AM
  • 551 views

Prioritizing Variants with Gene and Phenotype Knowledge

by Daniel Koboldt in Massgenomics

Exome and whole-genome sequencing offer powerful assays for disease diagnosis in clinical settings. In theory, they can help uncover the de novo mutations or inherited alleles responsible for rare genetic diseases. Over the past few years, several groups have developed strategies for filtering or prioritizing variants based on their likelihood to cause disease. Our tool, […]... Read more »

  • April 11, 2014
  • 12:46 PM
  • 673 views

Variant Annotation in Coding Regions

by Daniel Koboldt in Massgenomics

The analysis of NGS data comes with many challenges — data management, read alignment, variant calling, etc. — that the bioinformatics community has tackled with some success. Today I want to discuss another critical component of analysis that remains an unsolved problem: annotation of genetic variants. This process, in which we try to predict the […]... Read more »

Davis J McCarthy, Peter Humburg, Alexander Kanapin, Manuel A Rivas, Kyle Gaulton, The WGS500 Consortium, Jean-Baptiste Cazier and Peter Donnelly. (2014) Choice of transcripts and software has a large effect on variant annotation. Genome Medicine, 6(26). info:/doi:10.1186/gm543

  • March 11, 2014
  • 11:33 AM
  • 501 views

Variant Prioritization in Rare Mendelian Disorders

by Daniel Koboldt in Massgenomics

Few areas of biomedical research have benefited more from next-gen sequencing than studies of rare inherited diseases. Rapid, inexpensive exome sequencing in individuals with rare, presumably-monogenic diseases has been hugely successful over the past few years. There’s been a lot of discussion in the NGS community about the analysis burden of the large-scale whole-genome sequencing […]... Read more »

Koboldt DC, Larson DE, Sullivan LS, Bowne SJ, Steinberg KM, Churchill JD, Buhr AC, Nutter N, Pierce EA, Blanton SH.... (2014) Exome-Based Mapping and Variant Prioritization for Inherited Mendelian Disorders. American journal of human genetics. PMID: 24560519  

  • December 19, 2013
  • 10:47 AM
  • 989 views

Evolution and Transcription Factor Binding of Human Exons

by Daniel Koboldt in Massgenomics

A recent paper in Science has been hyped as the revelation of a new code affecting codon choice and protein evolution. In their study, Andrew Stergachis et al from the University of Washington applied DNAaseI-seq to map transcription factor occupancy across the human exome in 81 different cell types. They found that around 15% of […]... Read more »

Stergachis AB, Haugen E, Shafer A, Fu W, Vernot B, Reynolds A, Raubitschek A, Ziegler S, LeProust EM, Akey JM.... (2013) Exonic transcription factor binding directs codon choice and affects protein evolution. Science (New York, N.Y.), 342(6164), 1367-72. PMID: 24337295  

  • October 11, 2013
  • 12:58 PM
  • 541 views

Functional Variation Uncovered by Transcriptome Sequencing

by Daniel Koboldt in Massgenomics

It is increasingly clear that the annotation and interpretation of sequence variants represents one of the most important challenges in human genetics. With next-gen sequencing, our ability to identify variants — in disease pedigrees, case-control cohorts, and apparently healthy individuals — has rapidly outpaced our ability to say anything about what those variants do. This […]... Read more »

Lappalainen T, Sammeth M, Friedländer MR, 't Hoen PA, Monlong J, Rivas MA, Gonzàlez-Porta M, Kurbatova N, Griebel T, Ferreira PG.... (2013) Transcriptome and genome sequencing uncovers functional variation in humans. Nature, 501(7468), 506-11. PMID: 24037378  

  • September 17, 2013
  • 12:23 PM
  • 653 views

The role of alternative complement pathway in AMD

by Daniel Koboldt in Massgenomics

Three letters to Nature Genetics published (online) this week report the association of a rare nonsynonymous variant in the C3 gene with risk for age-related macular degeneration (AMD). These studies all came from different groups, working primarily with different case-control cohorts. What’s fascinating is how they all arrived at the same answer, at around the same time, but in very different ways. They also shared a starting point, of sorts: the relatively recent association of variants in ........ Read more »

Helgason H, Sulem P, Duvvari MR, Luo H, Thorleifsson G, Stefansson H, Jonsdottir I, Masson G, Gudbjartsson DF, Walters GB.... (2013) A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nature genetics. PMID: 24036950  

Zhan X, Larson DE, Wang C, Koboldt DC, Sergeev YV, Fulton RS, Fulton LL, Fronick CC, Branham KE, Bragg-Gresham J.... (2013) Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nature genetics. PMID: 24036949  

Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, Goldstein JI, Triebwasser M, Anderson HE, Zerbib J.... (2013) Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nature genetics. PMID: 24036952  

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