Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human traits and on other model organisms, including mouse, fly, nematode and yeast. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation.
Diverse neurodegenerative diseases share a common pathological feature, namely the accumulation of misfolded proteins. However, both drug development and research need more standardization of the biomarkers for the protein types involved. The bold strategy of integrating high-throughput genetic and chemical screens in yeast with experiments in neurons derived from genetically modified human induced pluripotent stem cells (iPSCs) is producing many significant new molecular insights into disease mechanisms.
Peripheral T cell lymphomas are rare but aggressive non-Hodgkin lymphomas derived from mature T lymphocytes or natural killer (NK) cells. New studies identify recurrent dominant-negative mutation of the RHOA GTPase gene in these lymphomas.
A new study explores the ancient oral microbiome from the well-preserved dental calculus samples of four human individuals who lived during medieval times, using a suite of genomic, proteomic and microscopic approaches. The authors investigate the evolution of dental pathogens by reconstructing the genome of the periodontal pathogen Tannerella forsythia and also identify antibiotic resistance genes, bacterial virulence factors and host immune defense proteins.
Genome-wide association studies have previously identified variants in SLC30A8, encoding the zinc transporter ZnT8, associated with diabetes risk. A rare variant association study has now established the direction of effect, surprisingly showing that loss-of-function mutations in SLC30A8 are protective against diabetes.
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.
Christian Steidl and colleagues identify recurrent somatic mutations in the PTPN1 gene in primary mediastinal B cell lymphoma and Hodgkin lymphoma. They show that mutant PTPN1 leads to reduced phosphatase activity and increased phosphorylation of JAK-STAT pathway members.
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.
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.
Helen Hobbs, Jonathan Cohen and colleagues identify a nonsynonymous variant in TM6SF2 associated with susceptibility to nonalcoholic fatty acid liver disease. They further show that knockdown of Tm6sf2 in mice results in increased liver triglyceride content and reduced very-low-density lipoprotein (VLDL) secretion, suggesting that impaired TM6SF2 function contributes causally to disease risk.
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.
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.
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.
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.
Frank Kooy, Nathalie Van der Aa and colleagues report that de novo mutations in ADNP cause a syndrome characterized by autism, intellectual disability and facial dysmorphisms. ADNP encodes a transcription factor that interacts with components of the SWI/SNF chromatin remodeling complex.
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.
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.
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.
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×.