Volume 44 Issue 4, April 2012

Neuroendocrine cells, including those in the gut, have a vast array of functions. A new study shows that conditional inactivation of the gene encoding Foxo1 in mouse intestinal endocrine cells converts them into cells synthesizing and secreting insulin. Ectopic gut insulin production was sufficient to ameliorate glucose control in mice with conditional pancreatic β-cell loss and diabetes mellitus.

A new study reports comparative genomic analysis of 52 geographically diverse strains of Chlamydia trachomatis. The authors reconstruct a genome-wide phylogeny of the species and report extensive genome-wide recombination across multiple lineages of this intracellular bacterial pathogen.

The reprogramming of somatic cells to a pluripotent state is prone to errors that could hamper the use of this technology. A new study now shows that vitamin C enhances the quality of somatic cell reprogramming in mice, highlighting the possibility that further manipulation of culture conditions could improve this technology for regenerative medicine.

Peter Visscher and colleagues report a new method for approximate conditional and joint association analysis that makes use of summary statistics from meta-analysis of GWAS. They apply this to meta-analysis summary data for height, body mass index and type 2 diabetes.

Naomichi Matsumoto and colleagues report mutations in the SWI/SNF chromatin remodeling complex in Coffin-Siris syndrome. Twenty affected individuals (87%) harbored mutations in one of six SWI/SNF subunit genes: SMARCB1, SMARCA4, SMARCA2, SMARCE1, ARID1A or ARID1B.

Gijs Santen and colleagues report mutations in the SWI/SNF subunit gene ARID1B in Coffin-Siris syndrome.

David Mitchell, Hannah Mitchison and colleagues identify a new Chlamydomonas protein required for the preassembly of axonemal dyneins before their transport into cilia. They further show that mutations in the homologous gene in humans result in primary ciliary dyskinesia accompanied by defects in the assembly of inner and outer dynein arms.

Michael Talkowski and colleagues examine karyotypically balanced genomic rearrangement landscapes in the germline at single-nucleotide resolution. They find predominant roles for complex reorganization and non-homologous repair in such 'chromothripsis' processes, suggesting a mechanism of template switching and blunt-end ligation.

Konrad Hochedlinger and colleagues show that ascorbic acid enhances cellular reprogramming by preventing hypermethylation of the imprinted Dlk1-Dio3 locus. They use this approach to generate adult mice derived entirely from induced pluripotent stem cells obtained through reprogramming of terminally differentiated B cells.

Domenico Accili and colleagues report that somatic ablation of Foxo1 in enteroendocrine progenitor cells leads to gut insulin-positive cells that have hallmarks of mature pancreatic β cells. Inactivating Foxo1 in the gut epithelium might provide a therapeutic mechanism for restoring insulin production in type 1 diabetes.

Simon Harris and colleagues report whole-genome sequencing of 36 Chlamydia trachomatis representative strains from temporally and geographically diverse sources and use this to construct a genome-wide phylogeny of the species. They find that epidemic spread can be driven by clonal expansion from a single source and also report evidence for recombination in recent clinical strains both within and between biovars.

Johannes Schödel and colleagues report the identification of a distant transcriptional enhancer of CCND1 at the recently identified renal cell carcinoma susceptibility locus at 11q13.3. The protective haplotype shows reduced binding of HIF-2α, reduced interaction with the transcriptional machinery and allelic imbalance in CCND1 expression. The study suggests that the hypoxia pathway is misregulated in renal cell carcinoma development.

Hidewaki Nakagawa and colleagues identify three new genetic loci associated with prostate cancer in Japanese.

Koichi Matsuda and colleagues show that common variants at the PSCA and ABO loci are associated with susceptibility to duodenal ulcer. The variant at PSCA associated with increased risk of duodenal ulcer is also associated with reduced risk of gastric cancer.

Cornelis Albers, Cedric Ghevaert and colleagues report that a majority of thrombocytopenia with absent radii (TAR) syndrome cases are caused by compound heterzygosity of a null allele and a low-frequency SNP in the regulatory regions of the RBM8A gene, which encodes the Y14 subunit of the exon-junction complex (EJC). TAR syndrome is the first reported human disorder caused by a defect in an EJC component.

William Dobyns, Daniela Pilz and colleagues show that de novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome, a developmental disorder characterized by distinct craniofacial features, ocular colobomata and defects in neuronal migration.

Joris Vermeesch, Raoul Hennekam and colleagues show that missense mutations in the SWI/SNF family member gene SMARCA2 cause Nicolaides-Baraitser syndrome, a disorder characterized by sparse hair, distinctive facial morphology, distal limb anomalies and intellectual disability. The mutations cluster to sequences encoding ultra-conserved motifs in the catalytic ATPase region of the protein and likely act in a dominant-negative or gain-of-function fashion.

Bjarne Udd and colleagues show that mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 result in limb-girdle muscular dystrophy. Their studies suggest that the mutations reduce the protective anti-aggregation effects of DNAJB6, leading to protein accumulation and autophagic pathology.

Xavier Jeunemaitre, Jean-Jacques Schott and colleagues report mutations of KLHL3 in familial hyperkalemic hypertension. KLHL3 encodes a BTB-BACK-kelch family actin-binding protein and regulates cell surface localization of the NaNa⁺-Cl⁻ cotransporter, a key regulator of ion resorption, at the distal nephron.

Olivier Delattre and colleagues report the discovery of a new subset of sarcoma defined by fusion of the BCOR and CCNB3 genes. By gene expression profiling, they show that BCOR-CCNB3–positive cases are biologically distinct from other sarcomas, particularly Ewing sarcoma.

To take advantage of hybrid vigor, most crop plants are grown with hybrid seeds, which are produced afresh by crossing elite inbred lines. Here, Erik Wijnker and colleagues demonstrate the feasibility of reverse breeding, a method that enables the generation of homozygous parental lines from a hybrid individual in the plant model organism Arabidopsis thaliana. Homozygous parents can be maintained indefinitely, better facilitating future improvements.