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Mike Stratton and colleague show that carriers of a germline copy number polymorphism involving APOBEC3A and APOBEC3B, which has been associated with increased risk of breast cancer, show more mutations characteristic of APOBEC-dependent mutational processes than cancers in non-carriers.
Kari Stefansson and colleagues performed a genome-wide association study for severe hand osteoarthritis and found associated variants within the ALDH1A2 gene and at 1p31.
Suzanne Baker, Jinghui Zhang and colleagues report the identification of recurrent somatic mutations in the bone morphogenetic protein (BMP) receptor ACVR1 in 32% of diffuse intrinsic pontine gliomas.
Nada Jabado and colleagues report identification of gain-of-function mutations in ACVR1, which encodes activin A receptor type I, in midline pediatric high-grade astrocytomas.
Eamonn Sheridan, Elizabeth Ross and colleagues report discovery of a new megalencephaly syndrome caused by de novo missense mutations in CCND2. They show that these mutations lead to stabilization of cyclin D2, and they present evidence that cyclin D2 stabilization may be a common downstream mechanism in PI3K-AKT–associated megalencephaly syndromes.
Yanick Crow, Sun Hur and colleagues show that gain-of-function mutations in IFIH1 cause a spectrum of neural and immunological phenotypes associated with enhanced interferon signaling. The mutations increase the affinity of IFIH1 for RNA, leading to immune upregulation and inflammatory disease.
De-Chen Lin, Ming-Rong Wang and colleagues report exome sequencing, RNA sequencing, and copy number analyses of esophageal squamous cell carcinoma. They identified recurrent mutations in FAT1, FAT2, ZNF750, EP300 and KMT2D.
Maria Teresa Landi and colleagues identify a rare missense variant in POT1 shared by five melanoma-prone families from Italy and associated with increased telomere length and telomere fragility. They also identify additional familial melanoma cases with rare missense variants in POT1 and find a significant excess of rare exonic POT1 variants in melanoma cases compared to controls, implicating POT1 variants in melanoma susceptibility.
Mario Falchi, Philippe Froguel and colleagues report association of a multi-allelic copy number variant encompassing the salivary amylase gene AMY1 with body mass index and risk of obesity.
David Adams, Julia Newton-Bishop, Timothy Bishop, Nicholas Hayward and colleagues identify loss-of-function variants in POT1 in several families with early onset multiple primary melanoma. They further show that these variants disrupt telomere binding by POT1 and are associated with increased telomere length.
Karolin Nord and colleagues report that GRM1 recombines with multiple genes in promoter swapping and gene fusion events in 90% of the chondromyxoid fibroma cases analyzed, resulting in GRM1 overexpression. These results implicate GRM1 rearrangement as a driver of CMF and a biomarker for this tumor type.
William Foulkes and colleagues identify germline inactivating mutations in familial cases of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Through additional analysis of non-familial tumors, the authors find that nearly 100% of tumors carry SMARCA4 mutations and 38 of 40 lack protein expression, implicating SMARCA4 loss as the major cause of SCCOHT.
Keith Caldecott, Bert de Vries, Sherif El-Khamisy, Gianpiero Cavalleri and colleagues identify homozygous TDP2 mutations in individuals with intellectual disability, seizures and ataxia. Their follow-up studies suggest that TDP2 is required to maintain normal transcription in response to the DNA double-strand breaks induced by abortive TOP2 activity.
Peter Campbell and colleagues identify PLCG1 and PTPRB as new driver genes for angiosarcoma through whole-exome sequencing of tumor samples. They find somatic PTPRB mutations in 10 of 39 cases and PLCG1 mutations in 3 of 34 cases, along with mutations in known cancer-related genes.
Yuqing He and colleagues show that Chalk5, a major quantitative trait locus for grain chalkiness in rice, encodes a vacuolar pyrophosphatase with H+ translocation activity. They find that elevated expression of Chalk5 disturbs the endomembrane trafficking system in developing seeds, leading to an accumulation of vesicle-like structures and increased chalkiness.
Nazneen Rahman, Katrina Tatton-Brown and colleagues identify de novo mutations in the DNA methyltransferase gene DNMT3A as the cause of a new overgrowth syndrome. Shared features of this syndrome include a distinctive facial appearance, intellectual disability and greater height.
Patrick H O'Farrell and colleagues show not only that deleterious variants are selected against but that complementing mutant mitochondria are selected at characteristic stable ratios.
Hong Xu and colleagues demonstrate reduced germline replication and selection against the transmission of mitochondria encoding a temperature-sensitive cytochrome c oxidase subunit.