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Ruth Halaban and colleagues report exome sequences of 147 melanoma tumors. They identified a recurrent somatic activating alteration in the Rho GTPase RAC1 in sun-exposed melanomas.
Shaoguang Li and colleagues show that the Blk pathway functions as a tumor suppressor in cancer stem cells of chronic myeloid leukemia but has no effect on normal hematopoietic stem cells. These results support the feasibility of selectively targeting leukemic stem cells without harming the normal stem cell compartment.
Evan Eichler and colleagues explore the structural diversity and ancestral origins of the 17q21.31 inversion region. They find that complex duplication architectures have arisen independently on both inversion haplotypes and have recently reached high frequencies among Europeans, either through extraordinary genetic drift or selective sweeps.
Trever Bivona and colleagues identify the upregulation of the AXL kinase in human non–small cell lung cancer with acquired resistance to erlotinib. Inhibition of AXL restores sensitivity to erlotinib in in vitro and in vivo tumor models. The authors suggest AXL as a potential therapeutic target that may prevent or overcome acquired resistance in patients with EGFR-mutant lung cancer.
James Brugarolas and colleagues identify recurrent BAP1 mutations in clear cell renal cell carcinoma (ccRCC). They show that BAP1 binds to HCF-1 and suppresses cell proliferation, and they find that BAP1 loss is associated with high tumor grade.
Eran Segal and colleagues measure the promoter activities of 70 different constructed promoter variants and find that poly(dA:dT) tracts significantly affect transcriptional outcome. They suggest that this is mediated by altering nucleosome organization and that these sequences can be manipulated to fine tune regulation of gene expression.
Claudia Langenberg, James Meigs and colleagues apply a joint meta-analysis approach that accounts for differences in body mass index to identify variants associated with glycemic traits. They report six new loci associated with fasting insulin levels and provide insights into the genetic basis of insulin resistance.
Luis Pérez-Jurado, Stephen Chanock and colleagues detect clonal chromosomal abnormalities in peripheral blood or buccal samples from individuals in the general population. They show that the frequency of such events increases with age and is associated with elevated risk of developing subsequent hematological cancers.
Cathy Laurie and colleagues detect mosaicism for large chromosomal abnormalities in peripheral blood in a subset of healthy individuals. They show that the frequency of such events increases with age and is associated with elevated risk of developing a subsequent hematological cancer.
Fernando Rivadeneira and colleagues in the Genetic Factors for Osteoporosis Consortium report a large-scale meta-analysis identifying new loci associated with bone mineral density (BMD) and risk of fracture. Thirty-two new loci are found to be associated with BMD, and 6 loci confer higher risk for low-trauma bone fracture.
Expression quantitative trait loci (eQTLs) are the genetic units of gene expression variation. Julian Knight and colleagues report an analysis of cell type–specific eQTLs from positively purified primary monocytes and B cells. Among the trans-acting eQTLs identified, they report new master regulators of gene expression, as well as autoimmune disease associations to specific HLA alleles.
Domenico Accili and colleagues report that somatic ablation of Foxo1 in enteroendocrine progenitor cells leads to gut insulin-positive cells that have hallmarks of mature pancreatic β cells. Inactivating Foxo1 in the gut epithelium might provide a therapeutic mechanism for restoring insulin production in type 1 diabetes.
Simon Harris and colleagues report whole-genome sequencing of 36 Chlamydia trachomatis representative strains from temporally and geographically diverse sources and use this to construct a genome-wide phylogeny of the species. They find that epidemic spread can be driven by clonal expansion from a single source and also report evidence for recombination in recent clinical strains both within and between biovars.
David Mitchell, Hannah Mitchison and colleagues identify a new Chlamydomonas protein required for the preassembly of axonemal dyneins before their transport into cilia. They further show that mutations in the homologous gene in humans result in primary ciliary dyskinesia accompanied by defects in the assembly of inner and outer dynein arms.
Konrad Hochedlinger and colleagues show that ascorbic acid enhances cellular reprogramming by preventing hypermethylation of the imprinted Dlk1-Dio3 locus. They use this approach to generate adult mice derived entirely from induced pluripotent stem cells obtained through reprogramming of terminally differentiated B cells.
Michael Talkowski and colleagues examine karyotypically balanced genomic rearrangement landscapes in the germline at single-nucleotide resolution. They find predominant roles for complex reorganization and non-homologous repair in such 'chromothripsis' processes, suggesting a mechanism of template switching and blunt-end ligation.
Eamonn Maher and colleagues report germline mutations in DIS3L2 causing the Perlman syndrome of overgrowth and susceptibility to Wilms tumor. DIS3L2 encodes a protein with exoribonuclease activity in the RNA exosome complex.
Samuli Ripatti and colleagues report a genome-wide association study for human serum metabolites using NMR of serum samples from over 8,000 Finnish individuals. They identify 31 loci associated with at least one of 216 serum metabolic measures.
Leonid Kruglyak and colleagues report high-throughput selective sequencing of a worldwide collection of 200 wild C. elegans strains, providing a comprehensive characterization of genetic variation in this species. They find that chromosome-scale selective sweeps have acted to reduce genetic variation and shape the C. elegans population structure in recent history.
Kathryn Lunetta and colleagues report a meta-analysis of 22 genome-wide association studies for age at menopause. They identify 13 loci newly associated with age at natural menopause, including several candidate genes with roles in DNA repair and immune function.