Editorial |
Featured
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News & Views |
Standardized phenotyping enhances Mendelian disease gene identification
Whole-exome sequencing has revolutionized the identification of genes with dominant disease-associated variants for rare clinically and genetically heterogeneous disorders, but the identification of genes with recessive disease-associated variants has been less successful. A new study now provides a framework integrating Mendelian variant filtering with statistical assessments of patients' genotypes and phenotypes, thereby catalyzing the discovery of novel mutations associated with recessive disease.
- Lisenka E L M Vissers
- & Joris A Veltman
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News & Views |
Gene signatures from pancreatic cancer tumor and stromal cells predict disease outcome
Pancreatic cancers consist of a heterogeneous amalgam of assorted cell types, making it challenging to develop a classification system that groups these tumors according to common molecular features. A new study tackles this important issue using bioinformatics approaches to decipher gene expression signatures derived specifically from either tumor cells or nonmalignant stromal cells that predict patient outcome and may inform personalized treatments.
- Filippos Kottakis
- & Nabeel Bardeesy
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Article |
Evidence of long-term gene flow and selection during domestication from analyses of Eurasian wild and domestic pig genomes
Laurent Frantz and colleagues report an analysis of 103 whole genomes from European and Asian wild boars and domestic pigs. They find evidence in support of a complex domestication model with gene flow from wild populations counteracted by recurrent artificial selection for traits important for domestication.
- Laurent A F Frantz
- , Joshua G Schraiber
- & Martien A M Groenen
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News & Views |
Genetic differential calculus
High-throughput analysis of the phenotypes of mouse genetic knockouts presents several challenges, such as systematic measurement biases that can vary with time. A report from the EUMODIC consortium presents data from 320 genetic knockouts generated using standardized phenotyping pipelines and new statistical analyses aimed at increasing reproducibility across centers.
- Richard Mott
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Technical Report |
In situ single-cell analysis identifies heterogeneity for PIK3CA mutation and HER2 amplification in HER2-positive breast cancer
Kornelia Polyak, Franziska Michor and colleagues report a novel method, STAR-FISH, for combined in situ single-cell analysis of point mutations and copy number alterations in archived tissue samples. They apply STAR-FISH to clinically relevant PIK3CA mutations and HER2 amplifications and observe associations between intratumoral diversity and clinical outcome.
- Michalina Janiszewska
- , Lin Liu
- & Kornelia Polyak
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News & Views |
Running spell-check to identify regulatory variants
A major challenge in human genetics is pinpointing which non-coding genetic variants affect gene expression and disease risk. A new study in this issue describes a broadly applicable approach for this task that explicitly models cell type–specific regulatory motifs and generates variant effect predictions that are more accurate and interpretable than those of alternative tools.
- Martin Kircher
- & Jay Shendure
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Article |
An in vivo screen identifies ependymoma oncogenes and tumor-suppressor genes
Richard Gilbertson and colleagues report an in vivo screen of 84 candidate oncogenes and 39 candidate tumor-suppressor genes in ependymoma mouse models. The validated targets are involved in vesicle trafficking, DNA modification and cholesterol biosynthesis.
- Kumarasamypet M Mohankumar
- , David S Currle
- & Richard J Gilbertson
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News & Views |
Symbiotic plant-fungi interactions stripped down to the root
Mycorrhizal fungi live in the roots of host plants and are crucial components of all forest ecosystems. A large-scale study of fungal genomics provides new insights into the evolution of mycorrhizae and a deep exploration of mycorrhizal diversity that helps to uncover the molecular and genetic details of fungal symbiotic relationships with plants.
- Luca Venturini
- & Massimo Delledonne
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Article |
Analysis of nascent RNA identifies a unified architecture of initiation regions at mammalian promoters and enhancers
John Lis, Adam Siepel and colleagues map transcription start sites across the genome in two human cell lines using a nuclear run-on protocol called GRO-cap. They find a common architecture of initiation at both promoters and enhancers and that transcript elongation stability provides the strongest distinction between promoters and enhancers.
- Leighton J Core
- , André L Martins
- & John T Lis
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Technical Report |
Haplotype-resolved whole-genome sequencing by contiguity-preserving transposition and combinatorial indexing
Frank Steemers and colleagues report a new method for genome-wide haplotyping based on contiguity-preserving transposition and combinatorial indexing. They apply this method to assemble over 95% of the heterozygous variants in a human genome into long, accurate haplotype blocks.
- Sasan Amini
- , Dmitry Pushkarev
- & Frank J Steemers
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Article |
Mouse tetrad analysis provides insights into recombination mechanisms and hotspot evolutionary dynamics
Scott Keeney, Bernard de Massy, Maria Jasin and colleagues report a method to perform tetrad analysis (analysis of all four chromatids from a single meiosis) in mouse and analyzed two recombination hotspots in mouse oocytes and spermatocytes. They show that gene conversion frequently spares the binding site of the hotspot-specifying protein PRDM9.
- Francesca Cole
- , Frédéric Baudat
- & Maria Jasin
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Correspondence |
miR-212 and miR-132 are dispensable for mouse mammary gland development
- Ahmet Ucar
- , Erdem Erikci
- & Kamal Chowdhury
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Editorial |
Little boxes
Our ability to map trait-associated regulatory variation still vastly exceeds the prospects for dissecting allele-specific effects on gene expression and activity in vivo in relevant tissues and organs. A small number of intensive investigations into functional variants should pave the way for scaleable strategies using high-throughput techniques and genomic data integration.
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News & Views |
Cross-talk between imprinted loci in Prader-Willi syndrome
Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes at an imprinted locus on chromosome 15, including the long noncoding RNA IPW. A new study identifies a critical role for IPW in modulating the expression of maternally expressed genes in trans, which has important implications for the understanding of imprinted gene networks.
- Adele Murrell
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Article
| Open AccessGenome sequence of the cultivated cotton Gossypium arboreum
Yu-Xian Zhu, Jun Wang, Shuxun Yu and colleagues report sequencing and assembly of the genome of cultivated cotton, Gossypium arboreum. Comparison with the Gossypium raimondii genome sequence provides insights into genome evolution and speciation, and identifies two shared whole-genome duplication events occurring before the speciation event around 2–13 million years ago.
- Fuguang Li
- , Guangyi Fan
- & Shuxun Yu
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Letter |
Direct measurement of transcription factor dissociation excludes a simple operator occupancy model for gene regulation
Johan Elf and colleagues developed a single-molecule chase assay to measure the time a single transcription factor is bound at a specific chromosomal operator site, which they use to examine the dynamics of binding of the Lac repressor dimer at the native lac operator in Escherichia coli. Their findings do not support the simple operator occupancy model and suggest a role for non-equilibrium transcription factor kinetics in E. coli gene regulation.
- Petter Hammar
- , Mats Walldén
- & Johan Elf
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Letter |
Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas
Adolfo Ferrando and colleagues report the exome sequencing of peripheral T cell lymphomas. They identified recurrent mutations in RHOA, TET2, DNMT3A, IDH2, FYN, ATM, B2M and CD58.
- Teresa Palomero
- , Lucile Couronné
- & Adolfo A Ferrando
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Letter |
Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas
Ludwine Messiaen and colleagues report the identification of constitutional LZTR1 mutations in individuals with schwannomatosis, an autosomal dominant inherited disorder of multiple schwannomas.
- Arkadiusz Piotrowski
- , Jing Xie
- & Ludwine M Messiaen
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Correspondence |
On the robustness of germ cell migration and microRNA-mediated regulation of chemokine signaling
- Mehdi Goudarzi
- , Ina Strate
- & Erez Raz
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Editorial |
Targeting molecular tumor types
In this issue, the Focus on Pan-Cancer Analysis examines the similarities and differences among the genomic and cellular alterations found in the first dozen tumor types to be profiled by The Cancer Genome Atlas (TCGA) Research Network. This first look across cancers offers new tools in genomics and bioinformatics and the prospect of repurposing targeted therapies to be directed by the molecular pathology of tumors in addition to their clinical classification.
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Article |
Massively parallel decoding of mammalian regulatory sequences supports a flexible organizational model
Nadav Ahituv and colleagues use a massively parallel reporter assay to test 4,970 synthetic regulatory element sequences, containing patterns of 12 known liver transcription factor binding sites, in mice and in HepG2 cells. They systematically test the impact of binding site copy number, spacing, combination and order on gene expression.
- Robin P Smith
- , Leila Taher
- & Nadav Ahituv
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Letter |
A genome-wide association study identifies two new cervical cancer susceptibility loci at 4q12 and 17q12
Ding Ma, Xing Xie, Yongyong Shi and colleagues report a genome-wide association study of cervical cancer in the Han Chinese population. They identify two new susceptibility lociat 4q12 and 17q12.
- Yongyong Shi
- , Li Li
- & Ding Ma
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