Research articles

Genome function is influenced by the three-dimensional organization of chromosomes. Kalhor et al. experimentally detect low-frequency intra- and interchromosomal interactions previously obscured by noise and use these data to model the genome architectures of populations of cells.

Over 90% of human whole-genome sequencing has been performed using instruments from two companies, Illumina and Complete Genomics. Lam et al. sequence the same DNA samples with both instruments and compare their performance for calling insertions, deletions and single-nucleotide variants.

Data filters separate true genetic variants in sequencing data from sequencing errors, but their effectiveness is difficult to assess. Reumers et al. use the genome sequences of monozygotic twins to evaluate the performance of filters individually and in combination, leading to a 290-fold reduction in error rate in calling single-nucleotide variants.

A catalog of genetic variation in a crop species facilitates marker-assisted breeding, gene mapping and analysis of elite traits. Xu et al. resequenced 40 cultivated and 10 wild rice accessions to >15 × coverage, yielding 6.5 million single-nucleotide polymorphisms and 808,000 small insertions and deletions.

Mouse induced pluripotent stem (iPS) cells have been shown to retain an epigenetic 'memory' of their cell type of origin. Kim et al. study this question in human cells and document both incomplete erasure of methylation and aberrant de novo methylation during reprogramming.

The International Stem Cell Initiative compares 125 ethnically diverse human embryonic stem cell lines at early and late passage. Data on karotype, single-nucleotide polymorphisms and methylation shed light on how the cells adapt to long-term culture.

Copy-number changes in cancer genomes may be caused by errors during the replication of colocalized DNA regions. De and Michor provide genome-wide evidence for this model by integrating data on DNA replication timing, the three-dimensional organization of the genome and copy-number alterations in cancer.

Copy-number changes, point mutations and rearrangements are all usually found in cancer genomes, but their relative frequencies are highly variable. Using statistical approaches to model different processes, Fudenberg et al. find that copy number gain and loss is influenced by the three-dimensional organization of the genome in the nucleus.

Rare transcripts remain enigmatic in part because they are difficult to detect robustly on a large scale. Mercer et al. show that targeted RNA sequencing after array capture can reach saturating depth at the targeted loci and reveal unprecedented levels of rare noncoding transcripts and previously unrecognized spliced variants from important loci such as p53 and HOX.

Not all cells in a tumor are alike, but our ability to characterize cancer heterogeneity in detail has been limited. Dalerba et al. use high-throughput single-cell expression analysis to define clinically relevant subpopulations in normal and cancerous colon tissue.

Creating synthetic biological circuits can be maddeningly difficult because of unpredictable stimuli and unknown variability in the system. Milias-Argeitis et al. circumvent these problems by moving control functions outside the cell—to a computer—and connecting computer and cell through optogenetics.

Pigeonpea is an important protein source in many developing countries, but limited genetic resources have constrained its improvement. The draft genome sequence of pigeonpea, the first for a nonindustrial crop and for a grain legume, should facilitate molecular breeding efforts to improve yields for subsistence farmers.

Davis et al. extend their previous efforts to use inhibitor-kinase interactions to understand kinase inhibitor selectivity by profiling the binding of 72 kinase inhibitors to 442 human kinase catalytic domains. The data reveal group-specific differences in selectivity and suggest the feasibility of developing reasonably specific inhibitors for most kinases.

The promiscuity of most kinase inhibitors can cause drug toxicity and complicate the interpretation of experiments. Rather than assessing kinase-compound binding, Anastassiadis et al. use functional assays to profile the activities of 178 commercially available kinase inhibitors against 300 recombinant human protein kinases.

Mass-release of sterile male mosquitoes is a promising option for controlling dengue and malaria, but it has never been shown that lab-raised transgenic males can compete effectively with their wild counterparts outside laboratory conditions. Promising results from a restricted field trail now suggest the feasibility of extending the approach for large-scale mosquito-control programs.

With the cost of DNA sequencing falling rapidly, sample preparation is becoming a bottleneck to surveying genetic variation across large populations or performing clinical diagnostics. Myllykangas et al. present an efficient approach for targeted sequencing in which genomic regions of interest are captured and sequenced inside a flow cell using a common oligonucleotide probe.

Cardiomyocytes generated from human pluripotent stem cells have many potential applications in drug screening, disease modeling and cell therapy. Dubois et al. describe a cell-surface marker that allows the isolation of highly enriched populations of cardiomyocytes from differentiation cultures.

Factor Xa would be ideally suited to control unregulated bleeding were it not for its extremely short half-life and tendency to overactivate clotting mechanisms. Ivanciu et al. show that a longer lived but less active variant of the protease restores hemostasis in mouse models of hemophilia without thrombotic complications.

The cynomolgus and Chinese rhesus macaques are used as animal models in biomedical research. Yan et al. sequence their genomes and compare the sequences to that of the Indian rhesus macaque, providing a genetic foundation for interpreting research results.

The benefits of crops that produce insecticidal toxins from Bacillus thuringiensis (Bt) are threatened by the emergence of insect resistance. Working with five major crop pests, Tabashnik et al. show that previously described variant Bt toxins kill pests rendered resistant to native Bt toxins by multiple mechanisms.