Volume 45 Issue 7, July 2013

Transposable elements (TEs) make up 50% of the human genome and are usually considered a mutational burden. A new study uses signatures of DNA hypomethylation to identify tissue-specific enhancers within TEs, providing fresh evidence that mobile DNA has a non-negligible role in genome regulation and evolution.

The discovery of new therapeutic targets and the personalization of treatments are two active areas of cancer research. New studies suggest that a 'co-clinical' approach may expedite both therapeutic target validation and risk stratification in patients with advanced prostate cancer.

A new study demonstrates that bacterial mutation rates associated with the Mycobacterium tuberculosis lineage most commonly linked to multidrug-resistant tuberculosis are multifold higher than shown in previous studies. This discovery, when considered together with recent findings on pharmacokinetic variability in patients, leads to new models of how multidrug-resistant tuberculosis arises, with direct therapeutic implications.

Adam Siepel and colleagues find that natural selection has exerted a significant influence on transcription factor binding sites in the human lineage using a new probabilistic method, INSIGHT. They analyzed whole-genome sequences from 54 individuals, as well as from several non-human primates, combined with chromatin immunoprecipitation and sequencing data sets to identify transcription factor binding sites and evidence of selection.

Matthew Brown and colleagues identify multiple susceptibility variants for ankylosing spondylitis through an association study based on high-density genotyping of immune-related loci. Their findings implicate numerous biological pathways in the pathogenesis of this disease and highlight shared risk factors with other autoimmune diseases.

The transcription factor Zbtb7a was previously described as an oncogene in non-Hodgkin lymphoma. Now, Pier Paolo Pandolfi and colleagues report that loss of Zbtb7a accelerates the progression of invasive prostate tumorigenesis in Pten-null mice and shows evidence of monoallelic loss in 18% of individuals with advanced prostate cancer.

Pier Paolo Pandolfi and colleagues report that compound loss of Pten with Zbtb7a or Trp53 leads to de novo resistance to androgen deprivation therapy in prostate cancer. Integrative analysis of mouse and human data in a co-clinical approach identified XIAP and SRD5A1 inhibitors as potential therapies for castration-resistant prostate cancer.

Eric Rahrmann and colleagues performed a transposon-based somatic mutagenesis screen for genes involved in malignant peripheral nerve sheath tumors (MPNSTs). They identified many recurrent transposon insertions and nominate Foxr2 as a new oncogene in MPNSTs.

The Rat Genome Sequencing and Mapping Consortium reports a combined sequence-based and genetic mapping analysis of 160 phenotypes in an outbred rat heterogeneous stock. They identify 31 genes involved in 27 different phenotypes.

Ning Li and colleagues report the whole-genome sequence of the duck, Anas platyrhynchos, a natural host of avian influenza viruses. They examine host response to infection by comparing the lung transcriptomes of ducks that were infected with influenza A viruses.

Sarah Fortune and colleagues report that Mycobacterium tuberculosis strains from lineage 2 acquire drug resistance in vitro more rapidly than strains from lineage 4 and show that this correlates with a higher in vivo mutation rate, as estimated from whole-genome sequencing of clinical isolates. They develop a stochastic mathematical model of the within-host evolution of drug resistance, using these mutation rate estimates to predict the rates of emergence of resistance in individuals with tuberculosis.

Timothy Chan and colleagues report exome and genome sequencing of 60 adenoid cystic carcinoma (ACC) tumor-normal pairs. They identify multiple pathways recurrently disrupted in ACC and provide evidence that KDM6A and PIK3CA are functionally relevant candidate ACC driver genes.

Sharon Savage and colleagues report the results of a genome-wide association study of osteosarcoma. They identify two susceptibility loci for this primary bone malignancy, including variants within the metabotropic glutamate receptor gene GRM4.

Jianjun Liu, Wei-Hua Jia, Adeline Seow, Dongxin Lin and colleagues report a genome-wide association study of B cell non-Hodgkin lymphoma in individuals of Chinese ancestry. They identify a new susceptibility locus on chromosome 3q27 in the intergenic region between BCL6 (B cell lymphoma protein 6) and LPP (lipoma preferred partner).

Andre Franke and colleagues perform an association study of atopic dermatitis based on high-density genotyping using the Immunochip array. They identify four new susceptibility loci for this common inflammatory skin disease.

Johannes van de Ven and colleagues report a rare missense mutation in CFI encoding a p.Gly119Arg substitution that confers a high risk of AMD. Sera from AMD cases carrying the p.Gly119Arg variant mediate the degradation of C3b at a significantly lower level than sera from AMD cases without the CFI variant.

Hongbing Shen, Zuomin Zhou, Yijiang Chen, Zhibin Hu and colleagues report genome-wide association analyses of sporadic non-syndromic congenital heart malformations in Han Chinese populations and identify two risk loci at 1p12 and 4q31.

Bernard Keavney, Judith Goodship and colleagues report a genome-wide association study of congenital heart disease and identify a region on chromosome 4p16 associated with risk of atrial septal defect.

Heather Mefford, Ingrid Scheffer and colleagues report targeted resequencing of 47 genes in 500 individuals with epileptic encephalopathies. They identify pathogenic mutations in 11% of their cohort and show that de novo mutations in CHD2 and SYNGAP1 cause epileptic encephalopathy.

Stephen Wright, Detlef Weigel and colleagues report the whole-genome sequence of Capsella rubella, a highly selfing crucifer found throughout much of southern and western Europe. They compare mixed-stage flower bud transcriptomes from C. rubella and C. grandiflora, finding a shift in expression of genes associated with flowering phenotypes and providing insights into the transition to selfing.

Ting Wang, Joseph Costello and colleagues report DNA methylation profiles of 11 human tissue types and show that DNA hypomethylation within specific transposable element families associates with tissue-specific enhancer activity.