A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep

Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov x Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation.     

Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24

Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 x 10(-4)). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer.     

Structural insight into antibiotic fosfomycin biosynthesis by a mononuclear iron enzyme

The biosynthetic pathway of the clinically important antibiotic fosfomycin uses enzymes that catalyse reactions without precedent in biology. Among these is hydroxypropylphosphonic acid epoxidase, which represents a new subfamily of non-haem mononuclear iron enzymes. Here we present six X-ray structures of this enzyme: the apoenzyme at 2.0 A resolution; a native Fe(II)-bound form at 2.4 A resolution; a tris(hydroxymethyl)aminomethane-Co(II)-enzyme complex structure at 1.8 A resolution; a substrate-Co(II)-enzyme complex structure at 2.5 A resolution; and two substrate-Fe(II)-enzyme complexes at 2.1 and 2.3 A resolution. These structural data lead us to suggest how this enzyme is able to recognize and respond to its substrate with a conformational change that protects the radical-based intermediates formed during catalysis. Comparisons with other family members suggest why substrate binding is able to prime iron for dioxygen binding in the absence of alpha-ketoglutarate (a co-substrate required by many mononuclear iron enzymes), and how the unique epoxidation reaction of hydroxypropylphosphonic acid epoxidase may occur.     

The binding of copper in human ceruloplasmin

Zusammenfassung Mit Photooxydation und Diazotierung wird gezeigt, dass Histidinreste an der Bindung von Kupfer an Caeruloplasmin beteiligt sind.     

Improving national-scale invasion maps: tamarisk in the western United States

New invasions, better field data, and novel spatial-modeling techniques often drive the need to revisit previous maps and models of invasive species. Such is the case with the at least 10 species of Tamarix, which are invading riparian systems in the western United States and expanding their range throughout North America. In 2006, we developed a National Tamarisk Map by using a compilation of presence and absence locations with remotely sensed data and statistical modeling techniques. Since the publication of that work, our database of Tamarix distributions has grown significantly. Using the updated database of species occurrence, new predictor variables, and the maximum entropy (Maxent) model, we have revised our potential Tamarix distribution map for the western United States. Distance-to-water was the strongest predictor in the model (58.1%), while mean temperature of the warmest quarter was the second best predictor (18.4%). Model validation, averaged from 25 model iterations, indicated that our analysis had strong predictive performance (AUC = 0.93) and that the extent of Tamarix distributions is much greater than previously thought. The southwestern United States had the greatest suitable habitat, and this result differed from the 2006 model. Our work highlights the utility of iterative modeling for invasive species habitat modeling as new information becomes available. A menudo las nuevas invasiones, mejores datos de campo y técnicas novedosas de modelado espacial impulsan la actualización de los mapas y de los modelos existentes de especies invasoras. Este es el caso de al menos 10 especies de Tamarix, las cuales están invadiendo los sistemas ribereños en el oeste de los EE.UU. y extendiendo su distribución por toda Norteamérica. En 2006, desarrollamos un mapa nacional del tamarisco (National Tamarisk Map) utilizando una compilación de sitios de presencia y ausencia con datos de sensores remotos y técnicas de modelación estadística. Desde la publicación de este trabajo, nuestra base de datos sobre la distribución de Tamarix ha crecido considerablemente. Utilizando la base de datos actualizada de presencia de especies, nuevas variables predictoras y el modelo de máxima entropía (Maxent), hemos modificado nuestro mapa de la distribución potencial de Tamarix para el oeste de los EE.UU. El predictor más fuerte en el modelo fue la distancia al agua (58.1%), y la temperatura promedio del trimestre más cálido fue el segundo (18.4%). La validación de modelo, calculada como el promedio de 25 iteraciones del modelo, indicó que nuestro análisis tuvo una alta capacidad predictiva (ABC = 0.93), y que la distribución de Tamarix es mucho más extensa de lo que se pensaba. El suroeste de los EE.UU. tuvo la mayor cantidad de hábitat adecuado para la especie, y este resultado difirió del modelo de 2006. Nuestro trabajo enfatiza la utilidad del modelado iterativo para modelar el hábitat de las especies invasoras a medida que se disponga de nueva información.     

HepaticΔ 4-steroid hydrogenase in the pregnant rat

Résumé Chez la rate gravide, la réduction du corticosterone, exprimé par gramme de foie fut augmentée les douzièmes et quatorzième jours de gestation. L'activité du foie entier augmenta à partir du douzième jour.     

IgH class switching and translocations use a robust non-classical end-joining pathway

Immunoglobulin variable region exons are assembled in developing B cells by V(D)J recombination. Once mature, these cells undergo class-switch recombination (CSR) when activated by antigen. CSR changes the heavy chain constant region exons (Ch) expressed with a given variable region exon from Cmu to a downstream Ch (for example, Cgamma, Cepsilon or Calpha), thereby switching expression from IgM to IgG, IgE or IgA. Both V(D)J recombination and CSR involve the introduction of DNA double-strand breaks and their repair by means of end joining. For CSR, double-strand breaks are introduced into switch regions that flank Cmu and a downstream Ch, followed by fusion of the broken switch regions. In mammalian cells, the 'classical' non-homologous end joining (C-NHEJ) pathway repairs both general DNA double-strand breaks and programmed double-strand breaks generated by V(D)J recombination. C-NHEJ, as observed during V(D)J recombination, joins ends that lack homology to form 'direct' joins, and also joins ends with several base-pair homologies to form microhomology joins. CSR joins also display direct and microhomology joins, and CSR has been suggested to use C-NHEJ. Xrcc4 and DNA ligase IV (Lig4), which cooperatively catalyse the ligation step of C-NHEJ, are the most specific C-NHEJ factors; they are absolutely required for V(D)J recombination and have no known functions other than C-NHEJ. Here we assess whether C-NHEJ is also critical for CSR by assaying CSR in Xrcc4- or Lig4-deficient mouse B cells. C-NHEJ indeed catalyses CSR joins, because C-NHEJ-deficient B cells had decreased CSR and substantial levels of IgH locus (immunoglobulin heavy chain, encoded by Igh) chromosomal breaks. However, an alternative end-joining pathway, which is markedly biased towards microhomology joins, supports CSR at unexpectedly robust levels in C-NHEJ-deficient B cells. In the absence of C-NHEJ, this alternative end-joining pathway also frequently joins Igh locus breaks to other chromosomes to generate translocations.     

Thymosin beta4 induces adult epicardial progenitor mobilization and neovascularization

Cardiac failure has a principal underlying aetiology of ischaemic damage arising from vascular insufficiency. Molecules that regulate collateral growth in the ischaemic heart also regulate coronary vasculature formation during embryogenesis. Here we identify thymosin beta4 (Tbeta4) as essential for all aspects of coronary vessel development in mice, and demonstrate that Tbeta4 stimulates significant outgrowth from quiescent adult epicardial explants, restoring pluripotency and triggering differentiation of fibroblasts, smooth muscle cells and endothelial cells. Tbeta4 knockdown in the heart is accompanied by significant reduction in the pro-angiogenic cleavage product N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP). Although injection of AcSDKP was unable to rescue Tbeta4 mutant hearts, it significantly enhanced endothelial cell differentiation from adult epicardially derived precursor cells. This study identifies Tbeta4 and AcSDKP as potent stimulators of coronary vasculogenesis and angiogenesis, and reveals Tbeta4-induced adult epicardial cells as a viable source of vascular progenitors for continued renewal of regressed vessels at low basal level or sustained neovascularization following cardiac injury.