111 posts · 116,790 views
Dan Koboldt blogs about human genetics, genomics, and DNA sequencing in the post-genome era.
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
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
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 »
Leslie, E., Taub, M., Liu, H., Steinberg, K., Koboldt, D., Zhang, Q., Carlson, J., Hetmanski, J., Wang, H., Larson, D.... (2015) Identification of Functional Variants for Cleft Lip with or without Cleft Palate in or near PAX7, FGFR2, and NOG by Targeted Sequencing of GWAS Loci. The American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2015.01.004
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
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
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 »
Yu JH, Harrell TM, Jamal SM, Tabor HK, & Bamshad MJ. (2014) Attitudes of genetics professionals toward the return of incidental results from exome and whole-genome sequencing. American journal of human genetics, 95(1), 77-84. PMID: 24975944
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 »
Tabor HK, Auer PL, Jamal SM, Chong JX, Yu JH, Gordon AS, Graubert TA, O'Donnell CJ, Rich SS, Nickerson DA.... (2014) Pathogenic variants for mendelian and complex traits in exomes of 6,517 European and african americans: implications for the return of incidental results. American journal of human genetics, 95(2), 183-93. PMID: 25087612
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 »
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
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
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