Positional cloning of Sorcs1, a type 2 diabetes quantitative trait locus

We previously mapped the type 2 diabetes mellitus-2 locus (T2dm2), which affects fasting insulin levels, to distal chromosome 19 in a leptin-deficient obese F2 intercross derived from C57BL/6 (B6) and BTBR T+ tf/J (BTBR) mice. Introgression of a 7-Mb segment of the B6 chromosome 19 into the BTBR background (strain 1339A) replicated the reduced insulin linked to T2dm2. The 1339A mice have markedly impaired insulin secretion in vivo and disrupted islet morphology. We used subcongenic strains derived from 1339A to localize the T2dm2 quantitative trait locus (QTL) to a 242-kb segment comprising the promoter, first exon and most of the first intron of the Sorcs1 gene. This was the only gene in the 1339A strain for which we detected amino acid substitutions and expression level differences between mice carrying B6 and BTBR alleles of this insert, thereby identifying variation within the Sorcs1 gene as underlying the phenotype associated with the T2dm2 locus. SorCS1 binds platelet-derived growth factor, a growth factor crucial for pericyte recruitment to the microvasculature, and may thus have a role in expanding or maintaining the islet vasculature. Our identification of the Sorcs1 gene provides insight into the pathway underlying the pathophysiology of obesity-induced type 2 diabetes mellitus.     

Epigenetic stem cell signature in cancer

Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.     

Identification of the cellular receptor for anthrax toxin.

The tripartite toxin secreted by Bacillus anthracis, the causative agent of anthrax, helps the bacterium evade the immune system and can kill the host during a systemic infection. Two components of the toxin enzymatically modify substrates within the cytosol of mammalian cells: oedema factor (OF) is an adenylate cyclase that impairs host defences through a variety of mechanisms including inhibiting phagocytosis; lethal factor (LF) is a zinc-dependent protease that cleaves mitogen-activated protein kinase kinase and causes lysis of macrophages. Protective antigen (PA), the third component, binds to a cellular receptor and mediates delivery of the enzymatic components to the cytosol. Here we describe the cloning of the human PA receptor using a genetic complementation approach. The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA. In addition, a soluble version of this domain can protect cells from the action of the toxin.     

Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus

We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.     

Constraints on convergence: hydrophobic hind legs allow some male pollinator fig wasps early access to submerged females

Pollinator fig wasps (Hymenoptera: Agaonidae) display numerous adaptations linked to their obligate association with fig trees (Ficus). Ceratosolen fig wasps pollinate figs that often fill temporarily with liquid, and one clade has males with unusually long hind legs. We investigated their morphology and behaviour. Scanning electron microscopy (SEM) revealed that the cuticle of their hind legs is highly modified and covered with numerous hydrophobic setae and microtrichia that can prevent blockage of the wasps’ large propodeal spiracles by liquids. In deep liquid, the males floated on the surface, but when only a thin layer of liquid was present, the legs allowed males to access females without the risk of drowning. Access to females was facilitated by an air bubble that forms between the hind legs and maintains a column of air between the spiracles and the centre of the figs. Sexual selection should favour males that can gain earlier access to mates, and the modified legs represent an adaptation to achieve this. Convergent adaptations are known in some unrelated non-pollinating fig wasps that develop in similar liquid-filled figs, but these species have enlarged hydrophobic peritremata at the ends of their metasoma to protect the spiracles located there. Unlike non-pollinating fig wasps, pollinator males need to insert their metasoma deep into females’ galls during mating. This difference in mating behaviour has constrained the extent of convergence.     

A report on two large collections of the squat lobster Munidopsis platirostris (Decapoda,Anomura, Munidopsidae) from the Caribbean,with notes on their parasites,associates, and reproduction

The reproduction and parasite associates of the squat lobster Munidopsis platirostris (A. Milne Edwards and Bouvier, 1894) were investigated based on collections made in the Bahamas and Curaçao with grassmat and bundled fishing net traps used to collect sipunculan worms and other small invertebrates. Size of ovigerous M. platirostris was significantly correlated with clutch size for females from both localities but females from the Bahamas produced significantly more eggs (on average 10.1 eggs/clutch) than females from Curaçao (on average 6.6 eggs/clutch). Early embryos of M. platirostris from the Bahamas were 0.74–0.82 mm in diameter, similar to some other species of Munidopsidae as well as Chirostylidae. Two species of crustaceans, another squat lobster and a leptostracan, as well as a limpet mollusc, were collected with M. platirostris in the Bahamas, while a sipunculan was an associated species in a Curaçao collection. One specimen of M. platirostris had an unidentified cryptoniscoid epicaridean isopod, possibly representing a new genus and species. Two specimens of M. platirostris each had one rhizocephalan externa of a species belonging to Lernaeodiscus Müller, 1862 but their morphology does not match that of L. schmitti Reinhard, 1950, the only species in the genus known from squat lobsters in the western Atlantic. Additional materials and tools, such as DNA analysis, are needed to describe these potentially new parasites and we suggest that use of these traps may be an effective method to obtain additional samples.     

Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians

We conducted a meta-analysis of genome-wide association studies of systolic (SBP) and diastolic (DBP) blood pressure in 19,608 subjects of east Asian ancestry from the AGEN-BP consortium followed up with de novo genotyping (n = 10,518) and further replication (n = 20,247) in east Asian samples. We identified genome-wide significant (P < 5 × 10(-8)) associations with SBP or DBP, which included variants at four new loci (ST7L-CAPZA1, FIGN-GRB14, ENPEP and NPR3) and a newly discovered variant near TBX3. Among the five newly discovered variants, we obtained significant replication in the independent samples for all of these loci except NPR3. We also confirmed seven loci previously identified in populations of European descent. Moreover, at 12q24.13 near ALDH2, we observed strong association signals (P = 7.9 × 10(-31) and P = 1.3 × 10(-35) for SBP and DBP, respectively) with ethnic specificity. These findings provide new insights into blood pressure regulation and potential targets for intervention.     

Dynamic harmonic regression

This paper describes in detail a flexible approach to nonstationary time series analysis based on a Dynamic Harmonic Regression (DHR) model of the Unobserved Components (UC) type, formulated within a stochastic state space setting. The model is particularly useful for adaptive seasonal adjustment, signal extraction and interpolation over gaps, as well as forecasting or backcasting. The Kalman Filter and Fixed Interval Smoothing algorithms are exploited for estimating the various components, with the Noise Variance Ratio and other hyperparameters in the stochastic state space model estimated by a novel optimization method in the frequency domain. Unlike other approaches of this general type, which normally exploit Maximum Likelihood methods, this optimization procedure is based on a cost function defined in terms of the difference between the logarithmic pseudo‐spectrum of the DHR model and the logarithmic autoregressive spectrum of the time series. The cost function not only seems to yield improved convergence characteristics when compared with the alternative ML cost function, but it also has much reduced numerical requirements. Copyright © 1999 John Wiley & Sons, Ltd.     

eIF2A,an initiator tRNA carrier refractory to eIF2α kinases,functions synergistically with eIF5B

The initiator tRNA (Met-tRNA _i ^Met ) at the P site of the small ribosomal subunit plays an important role in the recognition of an mRNA start codon. In bacteria, the initiator tRNA carrier, IF2, facilitates the positioning of Met-tRNA _i ^Met on the small ribosomal subunit. Eukarya contain the Met-tRNA _i ^Met carrier, eIF2 (unrelated to IF2), whose carrier activity is inhibited under stress conditions by the phosphorylation of its α-subunit by stress-activated eIF2α kinases. The stress-resistant initiator tRNA carrier, eIF2A, was recently uncovered and shown to load Met-tRNA _i ^Met on the 40S ribosomal subunit associated with a stress-resistant mRNA under stress conditions. Here, we report that eIF2A interacts and functionally cooperates with eIF5B (a homolog of IF2), and we describe the functional domains of eIF2A that are required for its binding of Met-tRNA _i ^Met , eIF5B, and a stress-resistant mRNA. The results indicate that the eukaryotic eIF5B–eIF2A complex functionally mimics the bacterial IF2 containing ribosome-, GTP-, and initiator tRNA-binding domains in a single polypeptide.