Articles in 2012

Cellular transformation in cancer has long been associated with aberrant DNA methylation, most notably, hypermethylation of promoter sequences. A new study uses a clever approach of selective high-resolution profiling to follow DNA methylation over a time course of cellular transformation and challenges the notion that hypermethylation in cancer arises in an orchestrated fashion.

Many SNPs associated with human disease are located in non-coding regions of the genome. A new study shows that SNPs associated with breast cancer risk are located in enhancer regions and alter binding affinity for the pioneer factor FOXA1.

Three papers characterizing human germline mutation rates bolster evidence for a relatively low rate of base substitution in modern humans and highlight a central role for paternal age in determining rates of mutation. These studies represent the advent of a transformation in our understanding of mutation rates and processes, which may ultimately have public health implications.

Industry and its regulators are increasingly finding value in inviting independent scrutiny of clinical trial data at the participant level. In addition to increasing accuracy and trust, accessible trial data can be used to generate new research hypotheses and validate existing research. Academic trial investigators need to be incentivized to catch up with this encouraging trend.

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.

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.

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.

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.

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.

Samuel Berkovic and colleagues report the identification of missense mutations in KCNT1, which encodes a sodium-gated potassium channel, that cause severe autosomal dominant nocturnal frontal lobe epilepsy.

Rima Nabbout and colleagues report the identification of de novo mutations in the KCNT1 potassium channel gene in individuals with malignant migrating partial seizures of infancy, a rare epileptic encephalopathy with pharmacoresistant seizures and developmental delay. The authors show that the mutations have a gain-of-function effect on KCNT1 channel activity.

Adrienne Flanagan and colleagues identify a common variant in the T gene associated with strong risk of chordoma, a rare malignant bone tumor. The risk variant alters an amino acid in the DNA-binding domain of the T transcription factor and is associated with differential expression of T and its downstream targets.

José Martin-Subero and colleagues report whole-genome bisulfite sequencing and methylome analysis of two CLLs and three B-cell subpopulations using high-density microarrays on 139 CLLs. They identify widespread hypomethylation in the gene body that is largely associated with intragenic enhancer elements.

Amos Tanay and colleagues characterize DNA methylation polymorphism within cell populations and track immortalized fibroblasts in culture for over 300 generations to show that formation of differentially methylated regions occurs through a stochastic process and nearly deterministic epigenetic remodeling.

Irwin McLean and colleagues report that heterozygous loss-of-function mutations in AAGAB, which encodes a cytosolic protein implicated in vesicular trafficking, cause punctate palmoplantar keratoderma. They further show that knockdown of AAGAB in keratinocytes leads to increased cell proliferation accompanied by highly elevated levels of epidermal growth factor receptor.

Mayumi Tamari and colleagues report a genome-wide association study for atopic dermatitis, a chronic inflammatory skin disease, in a Japanese population. They identify eight new susceptibility loci for atopic dermatitis and compare their results to those of previous studies in European and Chinese populations.

Patrick Chinnery, Nils-Goran Larsson and colleagues show that mitochondrial heteroplasmy levels are principally determined prenatally within the developing female germline in mice transmitting a heteroplasmic single base-pair deletion in the mitochondrial tRNA^Met gene.

Peter Gregersen and colleagues identify a regulatory variant in CSK, coding for an intracellular kinase that physically interacts with Lyp (PTPN22), associated with systemic lupus erythematosus (SLE). Their work suggests that the Lyp-Csk complex influences susceptibility to SLE through regulation of B-cell signaling, maturation and activation.

Jan Molenaar and colleagues show that LIN28B is overexpressed and amplified in human neuroblastomas and that LIN28B regulates let-7 family miRNAs and MYCN. They create a transgenic mouse model of LIN28B overexpression and show that these mice develop neuroblastoma tumors.

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.