Volume 43 Issue 9, September 2011

Advances in both pedigree-based and population-based genetic maps in recent years have helped unravel some of the mysteries of human meiotic recombination. The publication of the first admixture-derived human genetic maps offers a new approach for inferring recombination events and provides insight into variation in recombination rate patterns across populations.

A new study shows that the PTPN22 coding variant associated with autoimmunity is a loss-of-function allele that causes the protein tyrosine phosphatase encoded by PTPN22 to undergo accelerated degradation, resulting in enhanced signaling in several immune cell types.

Complex autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, psoriasis and inflammatory bowel disease have different pathological presentations but have overlapping genetic susceptibility variants. A new study using mice lacking Tnfaip3, whose ortholog is linked to autoimmune disease in humans, leads to insights in the role of one molecular driver of varied clinical symptomatology in disparate autoimmune disorders.

Richard Houlston, Matthias Simon and colleagues report that common variation at 10p12.31 influences meningioma susceptibility. The risk variants are located upstream of MLLT10, which encodes an activator of Wnt-dependent transcription.

Kenneth Kinzler and colleagues report exome sequencing of ten hepatocellular carcinoma tumors and matched normal tissue. They identify inactivating mutations in the chromatin remodeling gene ARID2 in a total of 9 out of 139 HCC tumors.

Laura Pasqualucci and Riccardo Dalla-Favera and colleagues report exome sequencing and copy-number analyses of diffuse large B-cell lymphomas. Their analyses identified mutations in genes not previously implicated in DLBCL pathogenesis, such as genes encoding chromatin modifiers such as MLL2.

Evan Eichler and colleagues analyze copy number variation in 15,767 children with intellectual disability, developmental delay, congenital birth defects and/or other related phenotypes. They identify 59 likely pathogenic CNV regions, including 14 new candidate regions, and estimate that ~14% of disorders in this sample collection are caused by large CNVs.

John Novembre and colleagues present a new approach for constructing recombination maps based on ancestry switch points among individuals. They construct a high-resolution genome-wide recombination map based on admixed African-American and African-Caribbean individuals and compare this to previous recombination maps.

Alexander van Oudenaarden and colleagues examine microRNA-mediated regulation of gene expression using single-cell measurements of a target gene's expression. They find that microRNAs can repress gene expression either as a switch or through fine-tuning and that the strength of repression can vary widely between cells.

Guy Rouleau, Marie-Odile Krebs and colleagues sequenced the exomes of 14 individuals with schizophrenia and their unaffected parents. Their findings support a role for de novo mutations in the etiology of schizophrenia and provide a list of genes that may contribute to disease pathogenesis.

Maria Karayiorgou, Joseph Gogos and colleagues sequenced the exomes of 53 sporadic schizophrenia cases and their parents as well as 22 unaffected control trios. They identified a large excess of non-synonymous de novo mutations in cases, supporting a role for de novo mutations in the etiology of this disease.

Jason Locasale, Lewis Cantley, Matthew Vander Heiden and colleagues show that PHGDH is amplified in some human cancers and diverts a relatively large amount of glycolytic carbon into serine and glycine biosynthesis. They further show that PHGDH-amplified cancer cells become dependent on PHGDH for their growth, suggesting that the altered metabolic flux driven by this amplification contributes to oncogenesis.

Zhiming Cai and colleagues report the exome sequencing of tumor and matched normal tissue from nine transitional cell carcinomas (TCCs) of the bladder, with further screening in 88 additional subjects. The authors identify mutations in chromatin remodeling genes in 59% of the 97 TCC subjects.

Nazneen Rahman and colleagues show that germline inactivating mutations in RAD51D confer susceptibility to ovarian cancer. They further show that RAD51D-deficient cells are sensitive to PARP inhibition, suggesting a possible strategy for treating cancers arising in RAD51D mutation carriers.

Leslie Biesecker and colleagues report exome sequencing of an individual with combined malonic and methylmalonic aciduria (CMAMMA). With follow-up sequencing of an additional eight cases, they confirm ACSF3 as a cause of CMAMMA. They further report a canine model for CMAMMA that has a mutation in a putative ACSF3 ortholog.

Dan Nicolae, Carole Ober and colleagues report a meta-analysis of genome-wide association studies for asthma in a collection of ethnically diverse North American populations. They identify a newly associated susceptibility locus at PYHIN1 in individuals of African descent.

Mayumi Tamari and colleagues report a genome-wide association study for adult asthma in a Japanese population. They identify three new asthma susceptibility loci.

Huai-Dong Song and colleagues report results of a genome-wide association study of Graves' disease. They confirm four previously reported risk loci for this disease and identify two new susceptibility loci at 4p14 and 6q27.

Katherine Siminovitch and colleagues show that mice expressing the autoimmune disease–associated Ptpn22 coding variant show thymic and splenic enlargement and lymphocyte and dendritic cell hyperresponsiveness. They further show that the variant promotes degradation of the protein, suggesting that it enhances autoimmune disease risk through a loss-of-function mechanism.

Geert van Loo, Rudi Beyaert, Dirk Elewaut and colleagues report that myeloid-specific deletion of Tnfaip3 in mice causes spontaneous destructive polyarthritis that resembles rheumatoid arthritis. Tnfaip3 encodes the A20 protein, which is involved in negative regulation of NF-κB signaling in response to proinflammatory stimuli.

Dong-Ha Oh and colleagues report the draft genome of the extremophile crucifer plant Thellungiella parvula. This species is endemic to highly saline environments subject to extreme temperatures. The genome was primarily assembled using next-generation sequencing data.