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Community microattribution review of the evidence for colon cancer risk conferred by constitutional variants in MLH1, MSH2, MSH6 and PMS2 has resulted in the reclassification of two-thirds of the variants reported in existing databases and led to clinical recommendations for the interpretation of 1,370 variants that do not result in obvious protein truncation.
Jessica Okosun, Csaba Bödör and colleagues performed whole-genome or whole-exome sequencing on 10 follicular lymphoma and transformed follicular lymphoma pairs, followed by deep sequencing of 28 target genes in an additional 122 cases. They identify recurrent mutations in linker histone genes and genes involved in JAK-STAT signaling, NF-κB signaling and B cell development.
Ludwine Messiaen and colleagues report the identification of constitutional LZTR1 mutations in individuals with schwannomatosis, an autosomal dominant inherited disorder of multiple schwannomas.
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.
Gonçalo Abecasis, Dajiang Liu and colleagues report a meta-analysis framework to identify rare variant associations based on gene-level tests and the use of shared summary statistics provided by individual studies. They demonstrate their approach on a meta-analysis of blood lipid levels including 18,699 individuals, drawn from across 7 studies and genotyped with exome arrays.
Michael Duchen, Francesco Muntoni, Eamonn Sheridan and colleagues show that loss-of-function mutations in MICU1 cause a recessive disorder characterized by proximal myopathy, learning difficulties and progressive extrapyramidal motor deficits. The mutations alter mitochondrial calcium homeostasis, leading to mitochondrial damage and dysfunction.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.