An integrated approach to characterize genetic interaction networks in yeast metabolism

Although experimental and theoretical efforts have been applied to globally map genetic interactions, we still do not understand how gene-gene interactions arise from the operation of biomolecular networks. To bridge the gap between empirical and computational studies, we i, quantitatively measured genetic interactions between ～185,000 metabolic gene pairs in Saccharomyces cerevisiae, ii, superposed the data on a detailed systems biology model of metabolism and iii, introduced a machine-learning method to reconcile empirical interaction data with model predictions. We systematically investigated the relative impacts of functional modularity and metabolic flux coupling on the distribution of negative and positive genetic interactions. We also provide a mechanistic explanation for the link between the degree of genetic interaction, pleiotropy and gene dispensability. Last, we show the feasibility of automated metabolic model refinement by correcting misannotations in NAD biosynthesis and confirming them by in vivo experiments.     

DNA repair is limiting for haematopoietic stem cells during ageing

Accumulation of DNA damage leading to adult stem cell exhaustion has been proposed to be a principal mechanism of ageing. Here we address this question by taking advantage of the highly specific role of DNA ligase IV in the repair of DNA double-strand breaks by non-homologous end-joining, and by the discovery of a unique mouse strain with a hypomorphic Lig4(Y288C) mutation. The Lig4(Y288C) mouse, identified by means of a mutagenesis screening programme, is a mouse model for human LIG4 syndrome, showing immunodeficiency and growth retardation. Diminished DNA double-strand break repair in the Lig4(Y288C) strain causes a progressive loss of haematopoietic stem cells and bone marrow cellularity during ageing, and severely impairs stem cell function in tissue culture and transplantation. The sensitivity of haematopoietic stem cells to non-homologous end-joining deficiency is therefore a key determinant of their ability to maintain themselves against physiological stress over time and to withstand culture and transplantation.     

Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.     

The signature of the first stars in atomic hydrogen at redshift 20

Dark and baryonic matter moved at different velocities in the early Universe, which strongly suppressed star formation in some regions. This was estimated to imprint a large-scale fluctuation signal of about two millikelvin in the 21-centimetre spectral line of atomic hydrogen associated with stars at a redshift of 20, although this estimate ignored the critical contribution of gas heating due to X-rays and major enhancements of the suppression. A large velocity difference reduces the abundance of haloes and requires the first stars to form in haloes of about a million solar masses, substantially greater than previously expected. Here we report a simulation of the distribution of the first stars at redshift 20 (cosmic age of around 180 million years), incorporating all these ingredients within a 400-megaparsec box. We find that the 21-centimetre hydrogen signature of these stars is an enhanced (ten millikelvin) fluctuation signal on the hundred-megaparsec scale, characterized by a flat power spectrum with prominent baryon acoustic oscillations. The required sensitivity to see this signal is achievable with an integration time of a thousand hours with an instrument like the Murchison Wide-field Array or the Low Frequency Array but designed to operate in the range of 50-100 megahertz.     

Identification of the gene for vitamin K epoxide reductase

Vitamin K epoxide reductase (VKOR) is the target of warfarin, the most widely prescribed anticoagulant for thromboembolic disorders. Although estimated to prevent twenty strokes per induced bleeding episode, warfarin is under-used because of the difficulty of controlling dosage and the fear of inducing bleeding. Although identified in 1974 (ref. 2), the enzyme has yet to be purified or its gene identified. A positional cloning approach has become possible after the mapping of warfarin resistance to rat chromosome 1 (ref. 3) and of vitamin K-dependent protein deficiencies to the syntenic region of human chromosome 16 (ref. 4). Localization of VKOR to 190 genes within human chromosome 16p12-q21 narrowed the search to 13 genes encoding candidate transmembrane proteins, and we used short interfering RNA (siRNA) pools against individual genes to test their ability to inhibit VKOR activity in human cells. Here, we report the identification of the gene for VKOR based on specific inhibition of VKOR activity by a single siRNA pool. We confirmed that MGC11276 messenger RNA encodes VKOR through its expression in insect cells and sensitivity to warfarin. The expressed enzyme is 163 amino acids long, with at least one transmembrane domain. Identification of the VKOR gene extends our understanding of blood clotting, and should facilitate development of new anticoagulant drugs.     

Endoparasites of the European ground squirrel (Spermophilus citellus) (Rodentia: Sciuridae) in central Macedonia,Greece

The European ground squirrel (Spermophilus citellus) is a small rodent categorized as vulnerable (IUCN). To investigate the parasitic fauna of this species in Greece, faecal samples from 125 animals belonging to six different populations were examined by standard parasitological methods. Parasites were found in 118 of the animals (94.4%). Oocysts of the coccidia Eimeria callospermophili were found in 92 animals (73.6%), Eimeria citelli in 76 (60.8%), Eimeria cynomysis in 41 (32.8%), Eimeria spp. (17.6%), Cryptosporidium spp. in 29 (23.2%), cysts of Entamoeba spp. in 32 animals (25.6%) and eggs of the trematode Brachylaima spp. in seven animals (5.6%). This is the first report of Entamoeba spp., Cryptosporidium spp. and Brachylaima spp. in S. citellus. The possible impact of these findings on the health status of S. citellus and the possible significance to domestic animals or public health is discussed.     

Parasites of the Lessepsian invasive fish Lagocephalus sceleratus (Gmelin 1789) in the eastern Mediterranean Sea

Lagocephalus sceleratus, is a Lessepsian invasive fish species introduced into the Mediterranean Sea through the Suez Canal. This study investigated it as host of parasites. Out of 41 individuals caught from northern and southern locations of the eastern Aegean Sea, nine were found to host parasites. Gnathia sp. praniza larva, an ectoparasite, was associated with severe damage of the primary and secondary structures of the gills and it was found in one specimen (prevalence 2.4%). Regarding endoparasites, Anisakis type I third-stage larvae were found in two specimens (prevalence 4.9%). In addition, adult nematodes of Hysterothylacium aduncum were found in another six specimens (prevalence 14.6%). Lagocephalus sceleratus is a new host for some indigenous parasites, with low host specificity, in the Mediterranean Sea, providing an additional niche for the success and increase of local populations of these parasites and, to our knowledge, this is the first record of L. sceleratus parasites in this area. Whether these parasites can control the invasion success of L. sceleratus needs to be further investigated. However, the low mean intensity of infection found in this study does not support such control.