Articles in 2015

Andrea Ventura and colleagues characterize an allelic series of genetically engineered mice harboring targeted deletions of individual members of the miR-17~92 cluster. They find evidence of functional cooperation and specialization among members of this cluster and show that the miR-17 seed family influences axial patterning.

Susanne Kohl and colleagues report mutations in ATF6, a regulator of the unfolded protein response pathway, that cause a familial form of achromatopsia. Their results indicate a role for ATF6 in foveal development rather than a direct role in the cone phototransduction pathway.

Da-Zhi Wang and colleagues knock out Trbp in mouse cardiomyocytes in vivo and investigate its requirement for normal heart function. They find that Trbp is necessary for the biogenesis of miR-208a, which targets and represses Sox6.

Zachary Lippman and colleagues report mutations in the tomato ortholog of CLV1 and a gene encoding a hydroxyproline O-arabinosyltransferase enzyme that modifies CLV3, both of which cause fasciated flowers and fruits owing to increased meristem size. They also find that a natural mutation in CLV3 was a major target of selection during tomato domestication.

Paul Boutros, Robert Bristow and colleagues report a molecular analysis of the spatial heterogeneity of clinically localized, multifocal prostate cancer. They find that multifocal tumors are highly heterogeneous, and they identify a novel recurrent amplification of MYCL1.

Gilean McVean and colleagues report the results of a large-scale clinical genome sequencing project spanning a broad spectrum of disorders. They identify factors influencing successful genetic diagnosis and highlight the challenges of interpreting findings for genetically heterogeneous disorders.

Eva Hoffman, Alan Handyside and colleagues generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female human meioses. They detect a reverse chromosome segregation pattern and selection for higher recombination rates in the female germ line and report chromosomal drive against non-recombinant chromatids at meiosis II.

Vanessa Wong and colleagues report whole-genome sequencing of 1,832 Salmonella enterica serovar Typhi isolates from 63 endemic countries. They identify mutations that define the multidrug resistant (MDR) H58 lineage and report numerous inter- and intracontinental transmissions of this lineage as well as an ongoing MDR typhoid epidemic in Africa.

Branden Moriarity, David Largaespada and colleagues report a Sleeping Beauty forward genetic screen in mice that identifies candidate genes and pathways for osteosarcoma tumor development and progression. They identify sites specifically associated with tumorigenesis and metastasis and find that several candidate oncogenes are involved in axon guidance.

Samuli Ripatti and colleagues report the results of a genome-wide association study for circulating lipid levels based on 1000 Genomes Project imputation. Their results implicate several new loci, refine the association signals at many established loci and highlight the impact of low-frequency variants on lipid traits.

Evan Eichler and colleagues analyze the relative impact of de novo and rare, inherited variants on autism risk. They show a statistically independent role for rare, inherited mutations and implicate several new candidate genes likely contributing to autism risk.

William Evans and colleagues find that the proinflammatory genes CASP1 and NLRP3 are expressed at higher levels in primary acute lymphoblastic leukemia cells that are resistant than in those that are sensitive to glucocorticoid treatment. They find that CASP1 mediates glucocorticoid resistance through cleavage of the glucocorticoid receptor.

Bin Han and colleagues report the draft genome sequence of the grass carp Ctenopharyngodon idellus, a major commercially farmed species of freshwater fish. Analyses of the grass carp genome identify lineage-specific duplications that may have contributed to the adaptation of this species to a vegetarian diet.

Nicholas Luscombe, Cameron Osborne and colleagues report the use of Capture Hi-C (CHi-C) to detect the long-range interactions of almost 22,000 promoters in 2 human cell types. They found that transcriptionally inactive genes interact with previously uncharacterized elements that may act as long-range silencers.

Seishi Ogawa, Atsushi Natsume and colleagues report analyses of large sets of sequence data of grade II and III gliomas. They find three distinct subtypes of grade II and III gliomas characterized by discrete mutation profiles and distinct clinical behaviors.

Nancy Jenkins, Neal Copeland and colleagues report the results of a Sleeping Beauty transposon mutagenesis screen in mice carrying a melanocyte-specific inducible Braf^V600E allele. Analysis of transposon insertion sites identified candidate genetic drivers of melanoma.

Timothy Bestor and colleagues disrupt the Fbxl10 gene in mice, which leads to dense de novo DNA methylation of promoters that are co-occupied by both FBXL10 and by Polycomb repressive complexes. They conclude that FBXL10 protects Polycomb-bound genes from hypermethylation.

Alexander Meissner and colleagues use CRISPR/Cas9 genome editing to inactivate the DNA methyltransferases DNMT1, DNMT3A and DNMT3B in human embryonic stem cells (ESCs). They find an essential role for DNMT1 in human ESCs and generate genome-wide maps of the DNA methylation changes that occur following inactivation of these enzymes.

Gabrielle Kardon and colleagues present a detailed study of diaphragm development in mice. They show that migration of connective tissue fibroblasts derived from the pleuroperitoneal folds controls diaphragm morphogenesis and that mosaic ablation of Gata4 in this cell population results in defects resembling human congenital diaphragmatic hernias.

Kari Stefansson and colleagues report the whole-genome sequencing of 2,636 individuals from Iceland to a median of 20× coverage, providing a valuable genomic resource for this population isolate. They characterize patterns of genetic variation and population structure and demonstrate the usefulness of this resource for genetic discovery for several disease phenotypes.