Articles in 2014

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.

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.

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.

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.

Jonathan Pritchard, Guy Sella and colleagues report an analysis using population genetic models to show that recent human demography is likely to have had little impact on the average burden of deleterious mutations. They examine two large exome sequence datasets and find that individuals of west African and European ancestry carry similar burdens of damaging mutations.

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.

Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.

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.

Charles Swanton and colleagues used multiregion exome sequencing to study the evolutionary histories of ten clear cell renal cell carcinomas. They observed marked intratumoral heterogeneity in all cases, with extensive evidence of parallel evolution of tumor subclones and only a small number of truncal driver events.

Tannishtha Reya and colleagues show that Lis1, a key mediator of asymmetric cell division, is required for blood formation and hematopoietic stem cell function. The authors also show that the directed control of asymmetric division is a critical regulator of malignant hematopoietic development.

Songlin Chen and colleagues sequenced the whole genomes of a male (ZZ) and a female (ZW) Chinese half-smooth tongue sole, Cynoglossus semilaevis. Their analysis provides insights into the structure and evolution of the sex chromosomes and adaptation to the benthic lifestyle of this flatfish.

Jay Shendure, Greg Cooper and colleagues report a framework for annotation of genetic variation, Combined Annotation–Dependent Depletion (CADD), integrating diverse annotations into a single C score. They show that C scores correlate with annotations of functionality, pathogenicity and experimentally measured regulatory effects.

A new study shows that HOXB13 is preferentially recruited to the risk allele of a prostate cancer–associated SNP, enhancing the expression of RFX6, a driver of prostate cancer cell migration and predictor of disease progression. The work illustrates how a single risk locus contributes both to prostate cancer incidence and, through functional follow-up, to disease progression.