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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.
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.
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.
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.
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.
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.
Mayumi Tamari and colleagues report a genome-wide association study for adult asthma in a Japanese population. They identify three new asthma susceptibility loci.
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.
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.
David Altshuler and colleagues compare strategies to fine map the association of common variants at 9p21 with type 2 diabetes and myocardial infarction. Their study provides an empirical assessment of the performance of targeted sequencing and imputation-based approaches to comprehensively assess genetic variation in disease-associated regions.
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.
Rosalind Eeles and colleagues report a multistage genome-wide association study of prostate cancer, identifying seven new prostate cancer susceptibility loci.
Kazuaki Chayama and colleagues report a genome-wide association study for progression to hepatocellular carcinoma in individuals with chronic hepatitis C. The authors identify a common variant within DEP2DC that is associated with risk of HCV-induced HCC.
Hongbing Shen and colleagues report a genome-wide association study for lung cancer in individuals of Han Chinese ancestry. The authors identify two new lung cancer susceptibility loci.
Gavin Kelsey and colleagues report methylation landscapes in mouse oocytes, sperm and blastocysts. They find that the majority of methylated CpG islands in oocytes display incomplete demethylation in preimplantation embryos.
Patrick Chinnery and colleagues analyze the effects on mitochondrial DNA of nucleoside analogue anti-retroviral (NRTIs) drugs in patients infected with HIV. The authors find that patients treated with commonly used NRTIs accumulate somatic mitochondrial DNA mutations in a process similar to normal aging.
Alberto Cascón, Mercedes Robledo and colleagues show that MAX germline mutations confer susceptibility to hereditary pheochromocytoma. This finding supports a key role for MAX and its interaction partners in tumors of neural crest cell origin.
Gerard Schellenberg and colleagues report a genome-wide association study for progressive supranuclear palsy, a movement disorder with prominent tau neuropathology. They identified three new risk loci and confirmed the known risk locus at MAPT.
Matthew Hurles and colleagues report the first direct comparative analysis of male and female germline mutation rates from whole-genome sequences of two parent-offspring trios sequenced as part of the 1000 Genomes Project. They identify variation in paternal and maternal mutation rates between these two families.