103 posts · 103,207 views
Dan Koboldt is works in the medical genomics group of The Genome Center at Washington University.
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 »
Singleton MV, Guthery SL, Voelkerding KV, Chen K, Kennedy B, Margraf RL, Durtschi J, Eilbeck K, Reese MG, Jorde LB.... (2014) Phevor combines multiple biomedical ontologies for accurate identification of disease-causing alleles in single individuals and small nuclear families. American journal of human genetics, 94(4), 599-610. PMID: 24702956
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
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
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
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
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
The genetics of inherited vision disorders — notably retinitis pigmentosa (RP) and age-related macular degeneration (AMD) — are an area of intense research. Numerous genes responsible for inherited retinopathies have been identified in the past ten years. At the time of writing, there are at least 242 different genetic disorders, with 202 different genes identified [...]... Read more »
There are only about 20,000 genes in the human genome, but they generate a surprising amount of diversity. Given that 0.1% of DNA sequence differs when any two individuals are compared, and only 4% differs when a human and a chimpanzee are compared, it’s clear that protein-coding differences alone can’t account for how we differ [...]... Read more »
Liang L, Morar N, Dixon AL, Lathrop GM, Abecasis GR, Moffatt MF, & Cookson WO. (2013) A cross-platform analysis of 14,177 expression quantitative trait loci derived from lymphoblastoid cell lines. Genome research, 23(4), 716-26. PMID: 23345460
Exome sequencing, which targets the exons of known protein-coding genes in the human genome, is being widely employed by the research community to determine the genetic basis of inherited disease. It’s rapidly becoming the frontline research tool in GWAS follow-ups, tumor-normal comparisons, and studies of Mendelian disorders. The authors of some publications have mistakenly referred [...]... Read more »
Rada-Iglesias A, & Wysocka J. (2011) Epigenomics of human embryonic stem cells and induced pluripotent stem cells: insights into pluripotency and implications for disease. Genome medicine, 3(6), 36. PMID: 21658297
About 1 in 8 women in the U.S. will develop breast cancer at some point in her lifetime. In 2013, an estimated 40,000 breast cancer deaths will occur in the U.S. and 300,000 women will be diagnosed with invasive or in situ malignancies. It’s not only one of the most common cancers, but it’s also [...]... Read more »
Gracia-Aznarez FJ, Fernandez V, Pita G, Peterlongo P, Dominguez O, de la Hoya M, Duran M, Osorio A, Moreno L, Gonzalez-Neira A.... (2013) Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles. PloS one, 8(2). PMID: 23409019
In last week's issue of Science, Melissa Gymrek and colleagues from the lab of Yaniv Erlich (Whitehead) report a method for the triangulation the identity of a sample donor using genomic data and public databases.
As a proof-of-principle, they uncovered the identities of about 50 sample donors from the CEPH Utah collection, perhaps the best-studied collection of "anonymous" samples to date. Their approach exploits several facts of this "information age" we live in.... Read more »
Gymrek M, McGuire AL, Golan D, Halperin E, & Erlich Y. (2013) Identifying personal genomes by surname inference. Science (New York, N.Y.), 339(6117), 321-4. PMID: 23329047
One of the burdens of the information age is that there’s far more content produced than could ever be read by the population. This is categorically true of blogging, but also a fact of research publication. With hundreds of academic journals (ISI indexes over 11,000 science and social science journals) and thousands of articles published [...]... Read more »
Tort, A., Targino, Z., & Amaral, O. (2012) Rising Publication Delays Inflate Journal Impact Factors. PLoS ONE, 7(12). DOI: 10.1371/journal.pone.0053374
Clinical genome sequencing holds great promise for the diagnosis and treatment of human disease, but also brings many ethical challenges. What if key variants are found in the genome of a patient who died? Should those results be returned to the family, and if so, how? [...]... Read more »
Chan, B., Facio, F., Eidem, H., Hull, S., Biesecker, L., & Berkman, B. (2012) Genomic Inheritances: Disclosing Individual Research Results From Whole-Exome Sequencing to Deceased Participants’ Relatives. The American Journal of Bioethics, 12(10), 1-8. DOI: 10.1080/15265161.2012.699138
It might surprise you to learn that the majority of genes found in human beings are not our own — they belong to the hundreds of species of bacteria that make up the gut microbiome. Just as the number of human genomes sequenced on next-gen instruments has grown exponentially in recent years, so too have [...]... Read more »
Schloissnig, S., Arumugam, M., Sunagawa, S., Mitreva, M., Tap, J., Zhu, A., Waller, A., Mende, D., Kultima, J., Martin, J.... (2012) Genomic variation landscape of the human gut microbiome. Nature. DOI: 10.1038/nature11711
This week marked an important milestone in our understanding of human genetic variation: the main publication of the 1,000 Genomes Project. The article in Nature describes the genomes from 1,092 individuals representing 14 populations across Europe, Africa, Asia, and the Americas. I think it’s important for anyone working in human genetics and genomics to read [...]... Read more »
The 1000 Genomes Project Consortium. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature. DOI: 10.1038/nature11632
Using genetic information to improve human health represents the central goal of biomedical research. Achieving it won’t be easy, but from a simplistic perspective, requires three steps. Cataloging the full extent of genetic variation in cells, tissues, and individuals. Efforts like the HapMap and 1,000 Genomes project are tackling this part, and judging by the [...]... Read more »
Now online at Nature is the most comprehensive molecular portrait of human breast tumors published to date. The Cancer Genome Atlas study encompasses more than 500 primary tumors representing the four intrinsic subtypes of breast cancer: Luminal A, Luminal B, Her2-enriched, and Basal-like. Using a suite of high-throughput platforms, TCGA characterized various aspects of these [...]... Read more »
The Cancer Genome Atlas Network. (2012) Comprehensive Molecular Portraits of Human Breast Tumors. Nature. DOI: 10.1038/nature11412
I’m still working through the outstanding series of articles published by members of the ENCODE Consortium. After my previous post highlighting their marker paper on genome content and function, I came across two companion papers that demonstrate the power of ENCODE data to characterize functional regulatory variants in the human genome. The first article, from [...]... Read more »
Vernot B, Stergachis AB, Maurano MT, Vierstra J, Neph S, Thurman RE, Stamatoyannopoulos JA, & Akey JM. (2012) Personal and population genomics of human regulatory variation. Genome research, 22(9), 1689-97. PMID: 22955981
Schaub MA, Boyle AP, Kundaje A, Batzoglou S, & Snyder M. (2012) Linking disease associations with regulatory information in the human genome. Genome research, 22(9), 1748-59. PMID: 22955986
Next-generation sequencing is a disruptive technology. It’s changed the way we conduct genetic and genomic research, and perhaps more importantly, where that research takes place. Because high-throughput sequencing is accessible not just to large genome centers but to the wider research community. With this “democratization” of sequencing, many things are changing. Virtually any investigator can [...]... Read more »
Yost SE, Smith EN, Schwab RB, Bao L, Jung H, Wang X, Voest E, Pierce JP, Messer K, Parker BA.... (2012) Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens. Nucleic acids research, 40(14). PMID: 22492626
Many, if not most human diseases have a genetic component. Thanks to advances in next-gen sequencing, a plethora of studies in recent years have shed light on the role of germline variants in heritable diseases, and of somatic mutations in cancer. They are also beginning to unravel the role of true de novo mutations — [...]... Read more »
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