Research articles

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.

Douglas Levine and colleagues identify recurrent inactivating mutations in the SWI/SNF complex member SMARCA4 in 12 of 12 samples of small cell carcinoma of the ovary, hypercalcemic type. These findings open the door for the development of targeted therapies to treat this rare but deadly cancer.

Jeffrey Trent, David Huntsman and colleagues identify the SWI/SNF chromatin-remodeling gene SMARCA4 as commonly mutated in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Their results implicate SMARCA4 as a crucial factor in the oncogenesis of SCCOHT, a rare but highly malignant cancer.

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.

Gonçalo Abecasis, Chaolong Wang and colleagues report a new statistical method, implemented in a publicly available software program LASER, to estimate an individual's genetic ancestry directly from off-target sequence reads from targeted sequencing experiments, making use of a reference panel. Their simulations and testing on real data sets show accurate inference of worldwide continental ancestry with whole-genome shotgun coverage as low as 0.001× and of fine-scale ancestry within Europe with coverage as low as 0.1×.

Cristen Willer, Kristian Hveem and colleagues use an exome array to identify a coding variant in TM6SF2 that is associated with total cholesterol levels. They further show that transient overexpression of TM6SF2 or knockdown of Tm6sf2 in mice alters serum lipid profiles, implicating TM6SF2 as a causal regulator of lipid traits.

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.

Richard Thompson, Melissa Sambrotta and colleagues show that biallelic mutations in TJP2 cause severe cholestatic liver disease. Their findings suggest that loss of TJP2 protein disrupts the structural integrity of tight junctions in liver tissue, resulting in progressive liver damage.

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.

Michelle Kelliher, Bradley Bernstein and colleagues identify T cell acute lymphoblastic leukemia cells that are resistant to γ-secretase inhibitor treatment and characterize the epigenetic mechanism of resistance.

David Altshuler and colleagues report genotyping or sequencing of ∼150,000 individuals from several population-based cohorts, identifying 12 rare protein-truncating variants in SLC30A8, encoding a pancreatic islet zinc transporter. Carriers of these rare protein-truncating variants in SLC30A8 show reduced risk of type 2 diabetes and reduced glucose levels.

Sanghyuk Lee, Young Hyeh Ko and colleagues report exome and transcriptome sequences for angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, and identify a recurrent somatic mutation in RHOA.

Johan Elf and colleagues developed a single-molecule chase assay to measure the time a single transcription factor is bound at a specific chromosomal operator site, which they use to examine the dynamics of binding of the Lac repressor dimer at the native lac operator in Escherichia coli. Their findings do not support the simple operator occupancy model and suggest a role for non-equilibrium transcription factor kinetics in E. coli gene regulation.

Christina Warinner and colleagues report a high-resolution characterization of the oral microbiome isolated from the dental tissues of adult skeletons dating to 1100 CE and showing evidence of periodontal disease. They show the long-term carriage of a diverse range of opportunistic pathogens in the oral cavity and reconstruct the genome of the periodontal pathogen Tannerella forsythia.