PAWE-3D: visualizing power for association with error in case-control genetic studies of complex traits

SUMMARY: A website that plots power and sample size calculations over a range of up to eight parameters (including diagnostic misclassification error parameters) for two commonly used statistical tests of genetic association, the linear trend test and the genotypic test of association. AVAILABILITY: This method is made available via the website http://linkage.rockefeller.edu/pawe3d/ CONTACT: pawe3d@linkage.rockefeller.edu.     

Watching tubules glow and branch

Branching morphogenesis is an important mechanism of animal development yet, until recently, most details about this highly dynamic process have had to be inferred from fixed tissues. Several groups have now developed transgenic animals in which branching tubules express fluorescent proteins, enabling their morphogenesis to be studied dynamically using time-lapse microscopy. The results have shown that branch emergence is highly variable, that sprouting tracheae and blood vessels guide themselves by filopodial projections, that branching morphogenesis can involve highly ordered cell rearrangements, and that branches are subject to intense remodelling. Though they are very new, these fluorescent systems have already expanded our knowledge of branching morphogenesis; future work, in which fluorescence might be used to report processes in addition to anatomy, promises an even greater advance.     

Structure-based design of protein tyrosine phosphatase-1B inhibitors

Using structure-based design, a new class of inhibitors of protein tyrosine phosphatase-1B (PTP1B) has been identified, which incorporate the 1,2,5-thiadiazolidin-3-one-1,1-dioxide template.     

Gene expression profiling of mouse host response to Listeria monocytogenes infection

The purpose of this study was to evaluate gene expression profiles in the liver and blood for prediction of infection severity from Listeria monocytogenes (LM). Mice were injected with medium broth (control) or a nonlethal or lethal dose of LM and sacrificed 6 h later. Gene expression changes were determined using Affymetrix MGU74Av2 GeneChips and confirmed by real-time polymerase chain reaction analysis. We identified discernable genes whose gene expression profiles can be used in pattern recognition to predict and classify samples in differently treated groups, with >or=90% accuracy in liver samples and 80% accuracy in blood at prediction; however, different genes were predictive in each tissue. Our results suggest that gene expression profiling in response to LM in mice may be able to distinguish samples in groups with varying severity of infection and provide information in finding molecular mechanisms and early biomarkers for subsequent conventional clinical endpoints.     

Visibility reflects dynamic changes of effective connectivity between V1 and fusiform cortex

Identifying the neural basis of visibility is central to understanding conscious visual perception. Visibility of basic features such as brightness is often thought to reflect activity in just early visual cortex. But here we show under metacontrast masking that fMRI activity in stimulus-driven areas of early visual cortex did not reflect parametric changes in the visibility of a brightness stimulus. The psychometric visibility function was instead correlated with activity in later visual regions plus parieto-frontal areas, and surprisingly, in representations of the unstimulated stimulus surround for primary visual cortex. Critically, decreased stimulus visibility was associated with a regionally-specific decoupling between early visual cortex and higher visual areas. This provides evidence that dynamic changes in effective connectivity can closely reflect visual perception.     

Population genetic analysis identifies source-sink dynamics for two sympatric garter snake species (Thamnophis elegans and Thamnophis sirtalis)

Population genetic structure can be shaped by multiple ecological and evolutionary factors, but the genetic consequences of these factors for multiple species inhabiting the same environment remain unexplored. We used microsatellite markers to examine the population structures of two coexisting species of garter snake, Thamnophis elegans and Thamnophis sirtalis, to determine if shared landscape and biology imposed similar population genetic structures. These snakes inhabit a series of ponds, lakes and flooded meadows in northern California and tend to converge on prey type wherever they coexist. Both garter snakes had comparable effective population sizes and bidirectional migration rates (estimated using a maximum-likelihood method based on the coalescent) with low but significant levels of genetic differentiation (F(ST) = 0.024 for T. elegans and 0.035 for T. sirtalis). Asymmetrical gene flow revealed large source populations for both species as well as potential sinks, suggesting frequent extinction-recolonization and metapopulation dynamics. In addition, we found a significant correlation between their genetic structures based on both pairwise F(ST)s for shared populations (P = 0.009) and for bidirectional migration rates (P = 0.024). Possible ecological and evolutionary factors influencing similarities and differences in genetic structure for the two species are discussed. Genetic measures of effective population size and migration rates obtained in this study are also compared with estimates obtained from mark-recapture data.     

Molecular evolution of the sheep prion protein gene

Transmissible spongiform encephalopathies (TSEs) are infectious, fatal neurodegenerative diseases characterized by aggregates of modified forms of the prion protein (PrP) in the central nervous system. Well known examples include variant Creutzfeldt-Jakob Disease (vCJD) in humans, BSE in cattle, chronic wasting disease in deer and scrapie in sheep and goats. In humans, sheep and deer, disease susceptibility is determined by host genotype at the prion protein gene (PRNP). Here I examine the molecular evolution of PRNP in ruminants and show that variation in sheep appears to have been maintained by balancing selection, a profoundly different process from that seen in other ruminants. Scrapie eradication programs such as those recently implemented in the UK, USA and elsewhere are based on the assumption that PRNP is under positive selection in response to scrapie. If, as these data suggest, that assumption is wrong, eradication programs will disrupt this balancing selection, and may have a negative impact on the fitness or scrapie resistance of national flocks.     

Linkage mapping reveals sex-dimorphic map distances in a passerine bird

Linkage maps are lacking for many highly influential model organisms in evolutionary research, including all passerine birds. Consequently, their full potential as research models is severely hampered. Here, we provide a partial linkage map and give novel estimates of sex-specific recombination rates in a passerine bird, the great reed warbler (Acrocephalus arundinaceus). Linkage analysis of genotypic data at 51 autosomal microsatellites and seven markers on the Z-chromosome (one of the sex chromosomes) from an extended pedigree resulted in 12 linkage groups with 2-8 loci. A striking feature of the map was the pronounced sex-dimorphism: males had a substantially lower recombination rate than females, which resulted in a suppressed autosomal map in males (sum of linkage groups: 110.2 cM) compared to females (237.2 cM; female/male map ratio: 2.15). The sex-specific recombination rates will facilitate the building of a denser linkage map and cast light on hypotheses about sex-specific recombination rates.     

Characterization of iron compounds in tumour tissue from temporal lobe epilepsy patients using low temperature magnetic methods

Excess iron accumulation in the brain has been shown to be related to a variety of neurodegenerative diseases. However, identification and characterization of iron compounds in human tissue is difficult because concentrations are very low. For the first time, a combination of low temperature magnetic methods was used to characterize iron compounds in tumour tissue from patients with mesial temporal lobe epilepsy (MTLE). Induced magnetization as a function of temperature was measured between 2 and 140 K after cooling in zero-field and after cooling in a 50 mT field. These curves reveal an average blocking temperature for ferritin of 10 K and an anomaly due to magnetite at 48 K. Hysteresis measurements at 5 K show a high coercivity phase that is unsaturated at 7 T, which is typical for ferritin. Magnetite concentration was determined from the saturation remanent magnetization at 77 K. Hysteresis measurements at various temperatures were used to examine the magnetic blocking of magnetite and ferritin. Our results demonstrate that low temperature magnetic measurements provide a useful and sensitive tool for the characterisation of magnetic iron compounds in human tissue.Published online: March 2005     

The metabolic effects of thia fatty acids in rat liver depend on the position of the sulfur atom

The effects on oxidation and composition of fatty acids in rat liver were compared after administration of fatty acids with sulfur substituted in different positions. It has been hypothesized that drugs with hydrophobic backbone have lipid-lowering effects because they are not easily catabolized by mitochondrial beta-oxidation. Thia fatty acids cannot be beta-oxidized when sulfur is in 3-position, but beta-oxidation is possible when sulfur is positioned further from the carboxyl group. To investigate whether catabolism of thia fatty acids would affect their ability to influence lipid metabolism, a series of thia fatty acids were synthesized and administered by oral gavage to male Wistar rats (300 mg/kg bodyweight/day for 7 days). Depending on the position of the sulfur atom and the chain length, the thia fatty acids were beta-oxidized, desaturated and/or elongated, and the accumulated amounts were lower as the sulfur atom were positioned further from the carboxyl group. All thia fatty acids led to high peroxisomal beta-oxidation of endogenous fatty acids, whereas the mitochondrial beta-oxidation was high when sulfur was in 3-position, low when sulfur was in 4-position and similar to controls when sulfur was in 5- or 7-position. The changes in hepatic fatty acid composition were more pronounced when sulfur was positioned close to the carboxyl group. In conclusion, both the position of the sulfur atom and the chain length appear to determine the catabolic fate of thia fatty acids, and the non-beta-oxidizable thia fatty acids were most potent in regulating oxidation and composition of endogenous fatty acids in rat liver.