Articles in 2013

Patrick Sullivan and colleagues report a multi-stage genome-wide association study for schizophrenia in a Swedish population. They identify 13 loci newly associated with schizophrenia.

Garry Cutting and colleagues report a comprehensive functional and clinical analysis of CFTR variants reported in cystic fibrosis. They determine that 128 of 160 CFTR variants with an allele frequency of >0.01% are causal for disease.

Sebastian Maerkl and colleagues use single-cell measurements to show that the output of the yeast PHO5 promoter can be precisely tuned by subtle changes in binding-site affinity for the Pho4 transcription factor. These results provide insights into how transcription-factor binding sites regulate gene expression and demonstrate the feasibility of developing quantitative models of transcriptional regulatory networks.

Anna Lasorella, Raul Rabadan, Antonio Iavarone and colleagues report an integrated analysis of genomic alterations in glioblastoma. They identify and functionally validate several new driver events, including loss-of-function mutations in CTNND2 and recurrent EGFR fusions.

Nadav Ahituv and colleagues use a massively parallel reporter assay to test 4,970 synthetic regulatory element sequences, containing patterns of 12 known liver transcription factor binding sites, in mice and in HepG2 cells. They systematically test the impact of binding site copy number, spacing, combination and order on gene expression.

Stefan Somlo and colleagues show that loss of intact cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease (ADPKD). They further show that the severity of cystic disease in these models is directly related to the length of time between the initial loss of polycystins and the subsequent involution of cilia, implicating a cilia-dependent cyst growth–promoting pathway in the pathogenesis of ADPKD.

Monica Justice and colleagues performed a genetic suppressor screen in Mecp2-null mice, which recapitulate symptoms of Rett syndrome, a neurological disease with autistic features. They identify a nonsense suppressor mutation in Sqle, which encodes a rate-limiting enzyme in cholesterol synthesis, and show that treatment of Mecp2 mutant mice with statins improves symptoms and increases longevity.

Heymut Omran, Joseph LoTurco and colleagues show that mutations in the dyslexia susceptibility candidate gene DYX1C1 cause primary ciliary dyskinesia. Their functional studies suggest that DYX1C1 is required for the cytoplasmic preassembly of axonemal dynein complexes.

Olivier Voinnet and colleagues characterize the sequence of molecular events underyling the activation, proliferation and eventual silencing of an endogenous retrotransposon in Arabidopsis thaliana. They further show how this transient mobilization causes widespread genome diversification and de novo epiallelism that could serve as sources of selectable and potentially adaptative traits.

Mathieu Blanchette and colleagues report whole-genome sequencing of three Brassicaceae species, Leavenworthia alabamica, Sisymbrium irio and Aethionema arabicum. They include comparative genomic analysis with 6 additional crucifier genomes, identify and characterize over 90,000 conserved noncoding sequences and provide a map of functional noncoding regions in plant genomes.

Seishi Ogawa and colleagues report an integrated genomics analysis of more than 100 clear-cell renal carcinoma samples. They analyze whole genomes or exomes, RNA sequences and DNA methylation in ∼100 paired specimens and perform SNP array-based copy number analysis for 240 specimens. They identify new recurrently mutated pathways and new associations between DNA methylation, mutations, gene expression and copy number profiles.

Magnus Nordborg and colleagues report sequencing of 180 Arabidopsis thaliana lines from Sweden. They characterize patterns of genetic variation and selection and provide a population resource that will be useful for association studies.

Susan Slager and colleagues report a meta-analysis of genome-wide association studies for chronic lymphocytic leukemia (CLL). They identify nine loci newly associated with CLL.

David Page and colleagues report that entry into meiosis is not required for oocyte development, which goes against previous concepts that entry into meiosis initiated oocyte differentiation and development. They show that mice lacking Stra8 fail in premeiotic replication and meiotic prophase.

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.

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.

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.

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.

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.

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.