Volume 44 Issue 12, December 2012

Two studies in this issue identify the landscape of somatic mutations in Burkitt lymphoma and highlight the pathogenic and clinical relevance of inactivating mutations of ID3, an inhibitor of the TCF3 transcription factor.

A new study shows that loss of the lariat debranching enzyme Dbr1 suppresses TDP-43 toxicity. The accumulated intronic lariat RNAs, which are normally degraded after splicing, likely act as decoys to sequester TDP-43 away from binding to and disrupting functions of other RNAs.

Powerful genomic technologies, such as exome sequencing, are providing new insights into the genetics underlying Mendelian traits. A new study identifies a role for digenic inheritance and an epigenetic modifier in facioscapulohumeral muscular dystrophy type 2.

Peter Donnelly and colleagues report fine mapping of 14 susceptibility loci in 8,000 cases and controls for type 2 diabetes, coronary artery disease and Graves' disease. They apply a new Bayesian method for analysis of fine-mapping data sets, using this to define sets of SNPs likely to contain causal disease-associated variants.

Aaron Gitler, Robert Farese Jr. and colleagues identify the RNA lariat debranching enzyme Dbr1 as a potent suppressor of TDP-43 toxicity in yeast. They further show that Dbr1 knockdown reduces TDP-43 toxicity in mammalian cells, identifying this enzyme as a possible therapeutic target in amyotrophic lateral sclerosis and other diseases marked by TDP-43 accumulation.

Daphne Bell and colleagues report exome sequences of serous endometrial tumors, a clinically aggressive subtype of endometrial cancer. The authors identified recurrent somatic mutations in CHD4, EP300, ARID1A, TSPYL2, FBXW7, SPOP, MAP3K4 and ABCC9.

Reiner Siebert and colleagues report whole-genome, whole-exome and transcriptome sequencing of Burkitt lymphomas. They identify recurrent mutations in several genes not previously known to be mutated in Burkitt lymphoma, including ID3, FBXO11, DDX3X and RHOA.

Sandeep Dave and colleagues report exome sequencing of 59 Burkitt lymphomas. They report recurrent mutations in many genes, including ID3, MYC, GNA13, RET, PIK3R1, NOTCH1 and the SWI/SNF genes ARID1A and SMARCA4.

Julius Gudmundsson, Kari Stefansson and colleagues identify a low-frequency variant at 8q24 strongly associated with prostate cancer risk. They also confirm association of a recently reported risk variant in HOXB13 in samples from multiple European populations.

Qing Lan and colleagues report the results of a genome-wide association study of lung cancer in never-smoking women from Asia. They identify three new susceptibility loci and confirm three other previously reported associations.

Jane Worthington and colleagues use a high-density genotyping chip to identify new susceptibility loci for rheumatoid arthritis and examine genetic overlap with other autoimmune diseases. Their results increase the number of confirmed rheumatoid arthritis risk loci in individuals of European ancestry and refine the location of many previously identified association signals to single genes.

Richard Trembath and colleagues report a meta-analysis of genome-wide association studies for psoriasis, including 2 cohorts genotyped on the custom Immunochip array, in a total of 10,588 cases and 22,806 controls. They identify 15 new susceptibility loci and refine signals in previously known loci, highlighting a role for innate host defense in susceptibility to psoriasis.

David Whitcomb, Bernie Devlin and colleagues report the results of a genome-wide association study of pancreatitis. They identify common variants at two loci associated with risk of this disease, including one on the X chromosome that shows strong evidence of interaction with alcohol consumption.

Dale Nyholt and colleagues report a genome-wide association meta-analysis of endometriosis in individuals of Japanese and European ancestry. They report a new susceptibility locus at 12q22 and establish an association at 2p25.1.

Simeon Boyadjiev and colleagues report a genome-wide association study of nonsyndromic sagittal craniosynostosis, the most common form of craniosynostosis. They identify risk loci near BMP2 on chromosome 20 and within BBS9 on chromosome 7.

Maria Karayiorgou, Joseph Gogos and colleagues report exome sequencing of 231 individuals with schizophrenia and their unaffected parents. They observed an excess of de novo nonsynonymous variants among probands and identified four genes (LAMA2, DPYD, TRRAP and VPS39) altered by recurrent de novo events.

Silvère van der Maarel, Stephen Tapscott, Daniel Miller and colleagues show that digenic inheritance of a mutation in SMCHD1 and a chromosome 4 haplotype permissive for DUX4 mRNA polyadenylation causes fascioscapulohumeral dystrophy type 2.

Daniel Bernard, Jan Wit, Mehul Dattani, Krishna Chatterjee and colleagues show that mutations in IGSF1 cause a new X-linked syndrome characterized by central hypothyroidism and testicular enlargement. Their findings implicate IGSF1 as a positive regulator of thyrotropin-releasing hormone signaling in the anterior pituitary.

Gerd Walz and colleagues use in vivo imaging in Xenopus laevis embryos and show that kidney tubule elongation occurs by a multicellular rosette-based mechanism, which has previously only been observed in Drosophila melanogaster. These data show that rosette-based cell intercalation is a highly conserved cellular mechanism during epithelial morphogenesis.

Robbie Waugh and colleagues report that the EARLINESS PER SE (EPS2) locus is associated with spring growth habit and environmental adaptation in barley. Resequencing the barley homolog of CENTRORADIALIS, located within the EPS2 locus, in 216 spring and 207 winter barley accessions identified haplotypes at HvCEN that correspond with winter or spring growth habit.

Variation in inflorescence architecture in plants affects reproductive success and agricultural yield. Zachary Lippman and colleagues report that the phenotype of the terminating flower (tmf) tomato mutant, the only known tomato mutant with single-flower inflorescence, is caused by a mutation affecting a nuclear protein that regulates known floral meristem identity complex members AN and FA to repress floral termination.