Articles in 2013

Boaz Cook and colleagues show that dominant disease-causing mutations in genes encoding P-type ATPases result in a gain-of-function ionic leakage phenotype that is exacerbated at elevated temperatures. The authors propose that the mutations promote leakage by disrupting the tight coupling of ATPase activity and transmembrane gating control.

Nancy Bonini and colleagues performed a genome-wide yeast screen for modifiers of TDP-43 toxicity and identified genes in RNA metabolism, including several RNA-binding proteins with connections to stress granules. They determined that therapeutic modulation of stress granule–associated eIF2α phosphorylation rescues TDP-43 toxicity in amyotrophic lateral sclerosis disease models in flies and primary mammalian neurons.

Neal Copeland and colleagues use a transposon mutagenesis screen to identify drivers of hepatocellular carcinoma in a mouse model of chronic hepatitis B infection. They find a very large number of candidate driver genes, many of which are implicated in cellular metabolism.

Margaret Goodell and colleagues report genome-wide mapping of 5-methylcytosine and 5-hydroxymethylcytosine in purified mouse hematopoietic stem cells. They identify large regions of low methylation with borders marked by 5-hydroxymethylcytosine. These borders become eroded in the absence of DNA methyltransferase 3a.

Augustine Kong, Kari Stefansson and colleagues report the discovery of common and low-frequency variants associated with genome-wide recombination rates. Most of the newly discovered variants exhibit differential effects on male and female recombination rates, and several map to genes with known roles in recombination, including RAD21L and MSH4.

Sarat Chandarlapaty and colleagues report the identification of mutations in the ESR1 gene affecting the ligand-binding domain of the encoded estrogen receptor in 20% of metastatic hormone-resistant breast cancers. They determine that the mutant receptor has a hormone-independent active state that likely promotes resistance to estrogen-depriving therapies.

Ruiqiang Li and colleagues report the whole-genome sequencing of a Tibetan female wild boar, as well as resequencing of 48 domestic pigs and wild boar from Tibet and China. Their analysis provides insights into the genetic diversity, population structure and evolution of the wild boar.

Kathy Sivils and colleagues report results of a large-scale association study of Sjögren's syndrome, a common autoimmune disease. They confirm strong associations with the HLA region and establish genome-wide significant associations at several non-HLA loci implicated in both innate and adaptive immunity.

Cristen Willer and colleagues report genome-wide association analyses for blood lipid levels in 188,578 individuals. They identify 62 loci newly associated with blood lipid levels, refine the association signals at 12 loci and examine associations with cardiovascular and metabolic traits.

Marco Sandri, Helge Amthor, Stefano Piccolo and colleagues show that BMP signaling is a key positive regulator of muscle hypertrophy. They further show that inhibiting BMP signaling causes muscle atrophy, abolishes the hypertrophic phenotype of myostatin knockout mice and exacerbates the effects of denervation and fasting.

Seishi Ogawa and colleagues report the landscape of somatic mutations in Down syndrome–related myeloid disorders. They identify recurrent mutations in multiple cohesin components, CTCF and epigenetic regulators in Down syndrome–related acute megakaryoblastic leukemia.

Magdalena Götz, Stephen Robertson and colleagues show that biallelic mutations in DCHS1 and FAT4 cause a multisystem disorder that includes periventricular neuronal heterotopia. They further show that reducing expression of Dchs1 and Fat4 in mouse embryonic neuroepithelium causes an increase in progenitor cell numbers and reduced neuronal differentiation, resulting in heterotopic accumulation of cells below the neuronal layers in the neocortex.

Ian Henderson and colleagues report fine-scale mapping and characterization of recombination rates in Arabidopsis thaliana. They find an enrichment of recombination hot spots overlapping transcription start and termination sites, as well as that hot spot–associated promoter regions show elevated levels of chromatin marks, including high H2A.Z, high H3K4me3 and low nucleosome density.

James Lupski and colleagues report a high-resolution analysis of 67 breakpoint junctions in 31 unrelated individuals with MECP2 duplication syndrome. They find that ~52% of genomic rearrangements in these individuals represent complex events in which the sequences flanking the breakpoints acquire additional changes, including small insertions, deletions and point mutations, likely resulting from error-prone DNA polymerase activity.

Alexander van Oudenaarden and colleagues analyze the temporal dynamics of the Caenorhabditis elegans transcriptome, reporting that ~2,000 genes show periodic expression oscillations in synchrony with progression through larval stages. They characterize the expression dynamics of the microRNA lin-4 and its target lin-14 and suggest that a microRNA-mediated feed-forward circuit is required for efficient dampening of expression oscillations to maintain the temporal gradient of the microRNA target.

Shengyue Wang and colleagues report the draft genome sequence and transcriptome analysis for Echinococcus granulosus, a parasitic helminth and cause of human hydatid disease. Their comparative genomic analysis identifies genes acquired by E. granulosus that are associated with host immune response, parasite survival and growth.

Iñaki Comas and colleagues report whole-genome sequencing and analysis of 259 Mycobacterium tuberculosis complex strains, providing a survey of global diversity and facilitating evolutionary analyses. Their phylogeographic analysis suggests the emergence of M. tuberculosis complex strains about 70,000 years ago in Africa, with expansion correlated with increased human population density during the Neolithic Demographic Transition.

Bing Ren and colleagues generate base-resolution maps of DNA methylation in 17 adult mouse tissues. They identify tissue-specific differentially methylated regions and show that they occur at distal cis-regulatory elements, many of which bear enhancer features.

David Alland and colleagues report sequencing of Mycobacterium tuberculosis strains under ethambutol drug selection. They follow the multistep progression in acquisition of ethambutol resistance in clinical isolates, finding that an interaction of mutations in several genes in DPA biosynthetic and utilization pathways influence the level of resistance as measured by the minimal inhibitory concentration.

Maha Farhat, Megan Murray and colleagues report whole-genome sequencing of 116 Mycobacterium tuberculosis strains selected to be representative of both global diversity and drug resistance. The authors develop a new method to search for resistance markers in microbial genomes based on reconstructing a genome-wide phylogeny and identifying regions showing convergent evolution, and they use this method to identify 39 new candidate drug resistance regions in the M. tuberculosis genome.