Extremely low-coverage sequencing and imputation increases power for genome-wide association studies

Genome-wide association studies (GWAS) have proven to be a powerful method to identify common genetic variants contributing to susceptibility to common diseases. Here, we show that extremely low-coverage sequencing (0.1-0.5×) captures almost as much of the common (>5%) and low-frequency (1-5%) variation across the genome as SNP arrays. As an empirical demonstration, we show that genome-wide SNP genotypes can be inferred at a mean r(2) of 0.71 using off-target data (0.24× average coverage) in a whole-exome study of 909 samples. Using both simulated and real exome-sequencing data sets, we show that association statistics obtained using extremely low-coverage sequencing data attain similar P values at known associated variants as data from genotyping arrays, without an excess of false positives. Within the context of reductions in sample preparation and sequencing costs, funds invested in extremely low-coverage sequencing can yield several times the effective sample size of GWAS based on SNP array data and a commensurate increase in statistical power.     

Effects of dopamine and ACTH on steroid sensitive single neurones in the basal hypothalamus

Zusammenfassung Mit Hilfe der Mikroelektrophorese wurde die Wirkung von Dexamethasonphosphat, Dopamin und ACTH lokal an Einzelneuronen des Hypothalamus der Ratte geprüft. Dexamethason-phosphat (ein synthetisches Corticosteroid) hemmte mehrheitlich die Aktivität der steroidempfindlichen Zellen im Hypothalamus, einige wenige dieser Zellen wurden aktiviert. Dopamin hemmte die Aktivität dieser steroidempfindlichen Neuronen sehr stark. ACTH dagegen aktivierte diese Zellen. Diese Resultate werden in Zusammenhang mit einem negativen und einem positiven «Feedback»-Mechanismus, der die ACTH-Bildung steuert, diskutiert.     

Myocardial function and energy metabolism in carnitine-deficient rats

Carnitine is essential for mitochondrial metabolism of long-chain fatty acids and thus for myocardial energy production. Accordingly, carnitine deficiency can be associated with cardiomyopathy. To better understand this disease, we determined myocardial function and energy metabolism in a rat model of carnitine deficiency. Carnitine deficiency was induced by a 3- or 6-week diet containing N-trimethyl-hydrazine-3-propionate, reducing cardiac and plasma carnitine by 70-85%. Myocardial function was investigated in isolated isovolumic heart preparations. Carnitine-deficient hearts showed left ventricular systolic dysfunction, reduced contractile reserve, and a blunted frequency-force relationship independently of the substrate used (glucose or palmitate). After glycogen depletion, palmitate could not sustain myocardial function. Histology and activities of carnitine palmitoyl transferase, citrate synthase, and cytochrome c oxidase were unaltered. Thus, as little as 3-6 weeks of systemic carnitine deficiency can lead to abnormalities in myocardial function. These abnormalities are masked by endogenous glycogen and are not accompanied by structural alterations of the myocardium or by altered activities of important mitochondrial enzymes.     

The influence of homologous plasma and fetal calf serum on human lymphocytic cortisol metabolism

Summary The influence of a) tissue culture medium (RPMI), b) homologous plasma (HP), and c) fetal calf serum (FCS) on lymphocytic cortisol metabolism was compared to that of phosphate buffered saline alone. RPMI was found to enhance the conversion rate 1.71 times, whereas HP and FCS enhanced it about 3.2 times. Raising the temperature of the HP and FCS to 100°C before incubation reduced the enhancing effect to the level of that obtained with RPMI.This work was supported by The Israel Cancer Research Fund N.Y. (George and Rose Blumenthal Research Fellowship for Hodgkins Disease). The authors are grateful to Dr Malchi and his staff from the Beilinson Hospital Blood Bank, for supplying us with buffy coats and to Mr Z. Klein for drawing the figure.     

Southern Ocean sea-ice extent, productivity and iron flux over the past eight glacial cycles

Sea ice and dust flux increased greatly in the Southern Ocean during the last glacial period. Palaeorecords provide contradictory evidence about marine productivity in this region, but beyond one glacial cycle, data were sparse. Here we present continuous chemical proxy data spanning the last eight glacial cycles (740,000 years) from the Dome C Antarctic ice core. These data constrain winter sea-ice extent in the Indian Ocean, Southern Ocean biogenic productivity and Patagonian climatic conditions. We found that maximum sea-ice extent is closely tied to Antarctic temperature on multi-millennial timescales, but less so on shorter timescales. Biological dimethylsulphide emissions south of the polar front seem to have changed little with climate, suggesting that sulphur compounds were not active in climate regulation. We observe large glacial-interglacial contrasts in iron deposition, which we infer reflects strongly changing Patagonian conditions. During glacial terminations, changes in Patagonia apparently preceded sea-ice reduction, indicating that multiple mechanisms may be responsible for different phases of CO2 increase during glacial terminations. We observe no changes in internal climatic feedbacks that could have caused the change in amplitude of Antarctic temperature variations observed 440,000 years ago.