Volume 46 Issue 10, October 2014

Meiotic tetrad analysis is a powerful tool for analyzing all four products of a single meiosis. A new method for tetrad analysis in mammals provides valuable insights into the mechanisms that mediate the exchange of DNA sequences between homologs during meiosis and their influence on the evolution of recombination hotspots.

A new study compares the copy number variants (CNVs) in 29,085 children with developmental delay to those in 19,584 healthy controls, providing a valuable compilation of such data. The phenotypic variability and wide range of penetrance for these variants present societal challenges regarding how these findings might be incorporated into newborn screening, early intervention and, perhaps, carrier testing and prenatal diagnosis.

The NLRC4 inflammasome mediates the rapid release of proinflammatory cytokines in response to various microbial stimuli, but its role in the pathology of human diseases remains unknown. Two new studies now report gain-of-function mutations in the NLRC4 gene that cosegregate with distinct autoinflammatory syndromes in affected families.

Charles Perou and colleagues apply a panel of 52 published gene expression signatures of human breast tumors to expression data from The Cancer Genome Project to identify new proliferation drivers. They find genomic regions that are uniquely amplified in highly proliferative luminal breast tumors, including some that are correlated with poor prognosis.

Paul Khavari and colleagues identify recurrent mutations concentrated at an ultraviolet signature hotspot in the KNSTRN gene in 19% of cutaneous squamous cell carcinomas. KNSTRN encodes a kinetochore protein.

Evan Eichler and colleagues report an expanded copy number variation (CNV) morbidity map of developmental delay, with additional resequencing of candidate genes in regions implicated by large CNVs. They identify several new disease-associated CNVs and show how their combined approach facilitates discovery of new developmental syndromes and disease genes.

Scott Keeney, Bernard de Massy, Maria Jasin and colleagues report a method to perform tetrad analysis (analysis of all four chromatids from a single meiosis) in mouse and analyzed two recombination hotspots in mouse oocytes and spermatocytes. They show that gene conversion frequently spares the binding site of the hotspot-specifying protein PRDM9.

Matthew Webster and colleagues report whole-genome sequencing of 140 honeybees from 14 worldwide populations. Their analyses provide insights into the evolutionary history and genetic basis of local adaptation in honeybees.

Stephen DiFazio and colleagues report the genome sequences and population genomic analyses of 544 black cottonwood trees (Populus trichocarpa) along the Northwest coast of North America. They find evidence for climate-driven selection on adaptive traits, including genes related to drought, photoperiod and stress.

Jie He and colleagues report exome sequencing of 113 tumor-normal pairs of esophageal squamous cell carcinoma. They highlight mutations in genes involved in cell cycle and apoptosis regulation, histone modifier genes and genes encoding members of the Hippo and Notch pathways.

Rosalind Eeles, Christopher Haiman and colleagues report genome-wide association and meta-analyses of prostate cancer in populations of European, African, Japanese and Latino ancestry. They identify 23 new susceptibility loci, including one associated with early-onset prostate cancer.

Dongxin Lin and colleagues report a genome-wide association study for laryngeal squamous cell carcinoma (LSCC) in Chinese populations. They identify three loci newly associated with LSCC.

Zhenglin Yang, Xinghuai Sun and colleagues report the results of a genome-wide association study of primary open-angle glaucoma in East Asians. They show that common variants near ABCA1 and in PPM2 are associated with increased risk of this disease.

Jamie Craig, Puya Gharahkhani and colleagues report results of a genome-wide association study of primary open-angle glaucoma. They identify common variants near ABCA1, AFAP1 and GMDS that are associated with risk of this disease.

Tin Aung, Christopher Hammond and colleagues report the results of a large genome-wide association study of intraocular pressure. They identify four new loci associated with this trait and show that three of these loci are associated with risk of primary open-angle glaucoma.

Graham Heap, Tariq Ahmad and colleagues show that common variants in the HLA-DQA1–HLA-DRB1 region confer susceptibility to thiopurine-induced pancreatitis in individuals undergoing treatment for inflammatory bowel diseases. These findings could help identify patients at risk of developing this serious adverse reaction to thiopurine therapy.

Richard Lifton, Barbara Kazmierczak and colleagues report the identification of a new enterocolitic and autoinflammatory syndrome, which they find is caused by de novo gain-of-function mutations affecting the inflammasome protein NLRC4. Cells with mutant NLRC4 produce elevated levels of cleaved caspase-1, which leads to cell death by pyroptosis.

Scott Canna and colleagues report the identification of a de novo mutation in a conserved region of NLRC4 by whole-exome sequencing of an individual presenting with macrophage activation syndrome. Functional studies confirm that the mutation leads to constitutive inflammasome activation.

Frank Uhlmann and colleagues show that the yeast Scc2–Scc4 cohesin loader complex is recruited to nucleosome-free regions in the promoters of highly expressed genes by the RSC chromatin remodeling complex and acts to maintain the nucleosome-free status of its binding sites. These findings suggest that human disorders caused by disruption of cohesin or RSC complex function, such as Cornelia de Lange and Coffin-Siris syndromes, could arise from related changes in the nucleosome landscape.