Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

Genome-wide association study of leaf architecture in the maize nested association mapping population

US maize yield has increased eight-fold in the past 80 years, with half of the gain attributed to selection by breeders. During this time, changes in maize leaf angle and size have altered plant architecture, allowing more efficient light capture as planting density has increased. Through a genome-wide association study (GWAS) of the maize nested association mapping panel, we determined the genetic basis of important leaf architecture traits and identified some of the key genes. Overall, we demonstrate that the genetic architecture of the leaf traits is dominated by small effects, with little epistasis, environmental interaction or pleiotropy. In particular, GWAS results show that variations at the liguleless genes have contributed to more upright leaves. These results demonstrate that the use of GWAS with specially designed mapping populations is effective in uncovering the basis of key agronomic traits.     

Systematic documentation and analysis of human genetic variation in hemoglobinopathies using the microattribution approach

We developed a series of interrelated locus-specific databases to store all published and unpublished genetic variation related to hemoglobinopathies and thalassemia and implemented microattribution to encourage submission of unpublished observations of genetic variation to these public repositories. A total of 1,941 unique genetic variants in 37 genes, encoding globins and other erythroid proteins, are currently documented in these databases, with reciprocal attribution of microcitations to data contributors. Our project provides the first example of implementing microattribution to incentivise submission of all known genetic variation in a defined system. It has demonstrably increased the reporting of human variants, leading to a comprehensive online resource for systematically describing human genetic variation in the globin genes and other genes contributing to hemoglobinopathies and thalassemias. The principles established here will serve as a model for other systems and for the analysis of other common and/or complex human genetic diseases.     

Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis

Hajdu-Cheney syndrome is a rare autosomal dominant skeletal disorder with facial anomalies, osteoporosis and acro-osteolysis. We sequenced the exomes of six unrelated individuals with this syndrome and identified heterozygous nonsense and frameshift mutations in NOTCH2 in five of them. All mutations cluster to the last coding exon of the gene, suggesting that the mutant mRNA products escape nonsense-mediated decay and that the resulting truncated NOTCH2 proteins act in a gain-of-function manner.     

Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1

We report a genome-wide association study for open-angle glaucoma (OAG) blindness using a discovery cohort of 590 individuals with severe visual field loss (cases) and 3,956 controls. We identified associated loci at TMCO1 (rs4656461[G] odds ratio (OR) = 1.68, P = 6.1 × 10(-10)) and CDKN2B-AS1 (rs4977756[A] OR = 1.50, P = 4.7 × 10(-9)). We replicated these associations in an independent cohort of cases with advanced OAG (rs4656461 P = 0.010; rs4977756 P = 0.042) and two additional cohorts of less severe OAG (rs4656461 combined discovery and replication P = 6.00 × 10(-14), OR = 1.51, 95% CI 1.35-1.68; rs4977756 combined P = 1.35 × 10(-14), OR = 1.39, 95% CI 1.28-1.51). We show retinal expression of genes at both loci in human ocular tissues. We also show that CDKN2A and CDKN2B are upregulated in the retina of a rat model of glaucoma.     

The sheddase activity of ADAM17/TACE is regulated by the tetraspanin CD9

ADAM17/TACE is a metalloproteinase responsible for the shedding of the proinflammatory cytokine TNF-α and many other cell surface proteins involved in development, cell adhesion, migration, differentiation, and proliferation. Despite the important biological function of ADAM17, the mechanisms of regulation of its metalloproteinase activity remain largely unknown. We report here that the tetraspanin CD9 and ADAM17 partially co-localize on the surface of endothelial and monocytic cells. In situ proximity ligation, co-immunoprecipitation, crosslinking, and pull-down experiments collectively demonstrate a direct association between these molecules. Functional studies reveal that treatment with CD9-specific antibodies or neoexpression of CD9 exert negative regulatory effects on ADAM17 sheddase activity. Conversely, CD9 silencing increased the activity of ADAM17 against its substrates TNF-α and ICAM-1. Taken together, our results show that CD9 associates with ADAM17 and, through this interaction, negatively regulates the sheddase activity of ADAM17.     

Biochemistry,evolution and physiological function of the Rnf complex,a novel ion-motive electron transport complex in prokaryotes

Microbes have a fascinating repertoire of bioenergetic enzymes and a huge variety of electron transport chains to cope with very different environmental conditions, such as different oxygen concentrations, different electron acceptors, pH and salinity. However, all these electron transport chains cover the redox span from NADH + H⁺ as the most negative donor to oxygen/H₂O as the most positive acceptor or increments thereof. The redox range more negative than −320 mV has been largely ignored. Here, we have summarized the recent data that unraveled a novel ion-motive electron transport chain, the Rnf complex, that energetically couples the cellular ferredoxin to the pyridine nucleotide pool. The energetics of the complex and its biochemistry, as well as its evolution and cellular function in different microbes, is discussed.     

Inflammasomes: current understanding and open questions

The innate immune system relies on its capability to detect invading microbes, tissue damage, or stress via evolutionarily conserved receptors. The nucleotide-binding domain leucine-rich repeat (NLR)-containing family of pattern recognition receptors includes several proteins that drive inflammation in response to a wide variety of molecular patterns. In particular, the NLRs that participate in the formation of a molecular scaffold termed the “inflammasome” have been intensively studied in past years. Inflammasome activation by multiple types of tissue damage or by pathogen-associated signatures results in the autocatalytic cleavage of caspase-1 and ultimately leads to the processing and thus secretion of pro-inflammatory cytokines, most importantly interleukin (IL)-1β and IL-18. Here, we review the current knowledge of mechanisms leading to the activation of inflammasomes. In particular, we focus on the controversial molecular mechanisms that regulate NLRP3 signaling and highlight recent advancements in DNA sensing by the inflammasome receptor AIM2.     

The apicomplexan plastid and its evolution

Protistan species belonging to the phylum Apicomplexa have a non-photosynthetic secondary plastid—the apicoplast. Although its tiny genome and even the entire nuclear genome has been sequenced for several organisms bearing the organelle, the reason for its existence remains largely obscure. Some of the functions of the apicoplast, including housekeeping ones, are significantly different from those of other plastids, possibly due to the organelle’s unique symbiotic origin.     

Biology of HLA-G in cancer: a candidate molecule for therapeutic intervention?

Although the expression of the non-classical HLA class I molecule HLA-G was first reported to be restricted to the fetal–maternal interface on the extravillous cytotrophoblasts, the distribution of HLA-G in normal tissues appears broader than originally described. HLA-G expression was found in embryonic tissues, in adult immune privileged organs, and in cells of the hematopoietic lineage. More interestingly, under pathophysiological conditions HLA-G antigens may be expressed on various types of malignant cells suggesting that HLA-G antigen expression is one strategy used by tumor cells to escape immune surveillance. In this article, we will focus on HLA-G expression in cancers of distinct histology and its association with the clinical course of diseases, on the underlying molecular mechanisms of impaired HLA-G expression, on the immune tolerant function of HLA-G in tumors, and on the use of membrane-bound and soluble HLA-G as a diagnostic or prognostic biomarker to identify tumors and to monitor disease stage, as well as on the use of HLA-G as a novel therapeutic target in cancer.