Volume 46 Issue 1, January 2014

Embryonal tumors with multilayered rosettes (ETMRs) are primitive neuroectodermal tumors arising in infants. A new study shows that these tumors are universally driven by fusion of the promoter of a gene with brain-specific expression, TTYH1, to C19MC, the largest human microRNA cluster, activating a fetal neural development program.

Only a few mutations in regulatory elements that cause human disease have been identified thus far. A new report identifies cis-regulatory mutations that abolish the activity of a developmental enhancer, thereby causing pancreatic agenesis.

To establish and maintain chronic infections, many pathogens adapt in response to selective pressures within the host, leaving unique genetic signatures. A new study uses whole-genome and population sequencing approaches to identify evidence of adaptive evolution in Burkholderia dolosa genomes isolated from chronic infections in patients with cystic fibrosis.

Paul Meltzer and colleagues report the results of an exome sequencing study of variant and IGHV4-34–expressing hairy-cell leukemias. They identify a high frequency of activating MAP2K1 mutations in these malignancies, suggesting potential therapeutic strategies.

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.

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.

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.

David Adams and colleagues identify inactivating mutations in CUX1 in diverse human cancers. They validate CUX1 as a tumor suppressor using mouse and Drosophila cancer models, and show that CUX1 deficiency activates phosphoinositide 3-kinase signaling through transcriptional downregulation of a PI3K inhibitor.

Nada Jabado, Jacek Majewski, Annie Huang and colleagues show that embryonal tumors with multilayered rosettes are characterized by a recurrent fusion of TTYH1 with the C19MC microRNA cluster. They further show that this fusion results in massive overexpression of a brain-specific isoform of DNMT3B, suggesting that this pediatric brain tumor is driven by epigenetic reactivation of an early developmental neurogenesis program.

Xuejun Zhang, Jun Wang and colleagues report the application of exome sequencing to a large collection of psoriasis cases and controls. They identify seven common and low-frequency nonsynonymous variants within known psoriasis susceptibility genes that are associated with psoriasis risk.

Klaus Bønnelykke and colleagues identify a common variant in CDHR3 associated with early childhood asthma with severe exacerbations. CDHR3 encodes a cell adhesion protein expressed at high levels in airway epithelium, suggesting a role for altered epithelial integrity in asthma pathogenesis.

Richard Houlston and colleagues report results of a genome-wide association study of chronic lymphocytic leukemia. They validate several new susceptibility loci for this disease, including variants near POT1, TERC and TERT.

Andrew Hattersley, Jorge Ferrer and colleagues use epigenomic annotation of pancreatic progenitor cells to guide the interpretation of whole-genome sequences from individuals with isolated pancreatic agenesis. They show that recessive mutations in a distal developmental enhancer of PTF1A cause pancreatic agenesis and abolish enhancer activity.

Florent Soubrier and colleagues identify biallelic mutations in EIF2AK4 as a major cause of pulmonary veno-occlusive disease, a rare form of pulmonary hypertension. EIF2AK4 encodes a serine-threonine kinase, and the disease-causing mutations are predicted to result in loss of protein function.

Sérgio Sousa and colleagues show that Lenz-Majewski syndrome, a disorder featuring generalized craniotubular hyperostosis, results from de novo gain-of-function mutations in PTDSS1. The mutations lead to increased phophatidylserine synthesis, suggesting a link between phosphatidylserine production and bone metabolism.

Wolfgang Busch and colleagues report results of a genome-wide association study of developmental cell–type traits in Arabidopsis. They identify a new F-box gene, KUK, as a regulator of root meristem and cell length and show the feasibility of applying genome-wide association to the study of cellular traits.

Roy Kishony and colleagues sequenced the genomes of Burkholderia dolosa isolates from patients with cystic fibrosis, using colony resequencing and deep population sequencing approaches to allow comparisons of multiple isolates from each individual. They identify extensive intrastrain genomic diversity and show specific signatures of selection acting on the pathogen within individual patients.

Jung-Hyun Lee, Jong Bhak and their colleagues report the whole-genome sequencing and de novo assembly of a male minke whale genome, as well as the genome sequences of three additional minke whales, a fin whale, a bottlenose dolphin and a finless porpoise. Their comparative analysis across cetaceans provides insights into adaptation to an aquatic lifestyle.