Research articles

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.

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.

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.

Kálmán Tory, Corinne Antignac and colleagues report that a variant of NPHS2, encoding p.Arg229Gln, causes nephrotic syndrome only when present in trans with particular mutations in the 3′ coding region of NPHS2. Mechanistically, the authors show that these 3′ mutations behave as recessive alleles when present with wild-type NPHS2 but exert a dominant-negative effect on the p.Arg229Gln variant, resulting in protein mislocalization.

Stephen Bentley, Paul Turner and colleagues report whole-genome sequencing of 3,085 pneumococci collected from a densely sampled pneumococcal carriage cohort in a Thai refugee camp over a 3-year period. They provide a high-resolution analysis of natural pneumococcal evolution and bacterial recombination, identifying lineage-specific variation in recombination.

Tao Cheng, Qian-fei Wang, Gang Huang and colleagues identify recurrent somatic loss-of-function mutations in SETD2 in individuals with acute leukemia. SETD2 encodes a histone H3K36 methyltransferase, and loss of SETD2 function causes global loss of H3K36 trimethylation and promotes leukemia stem cell self renewal.

Unnur Thorsteinsdottir, Kari Stefansson and colleagues identify low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. The newly discovered variants include an intronic variant associated with altered expression of CCND2, two independent missense variants in PAM and a rare frameshift variant in PDX1.

Adolfo Ferrando and colleagues report the exome sequencing of peripheral T cell lymphomas. They identified recurrent mutations in RHOA, TET2, DNMT3A, IDH2, FYN, ATM, B2M and CD58.

Sandro Santagata, Gad Getz and colleagues report the discovery of a recurrent mutation in the oncogene BRAF in papillary craniopharyngiomas that does not occur in the histologically related adamantinomatous form. Their results have the potential to aid in diagnosis and treatment of these intracranial tumors.

Shigeru Chiba and colleagues report exome sequencing of angioimmunoblastic T cell lymphoma (AITL) and other peripheral T cell lymphomas and identify a recurrent somatic RHOA mutation encoding a p.Gly17Val alteration in 68% of AITL samples.

Neil Hunter and colleagues show that the HEI10 ubiquitin ligase regulates meiotic recombination by limiting the colocalization of RNF212 and MSH4-MSH5 to future crossover sites. At later stages, they find that HEI10 accumulates stably at designated crossover sites and facilitates clearance of RNF212 and MSH4-MSH5 complexes to promote the final steps of meiotic recombination.