Nat Genet

The function of the majority of genes in the mouse and human genomes remains unknown. The mouse embryonic stem cell knockout resource provides a basis for the characterization of relationships between genes and phenotypes. The EUMODIC consortium developed and validated robust methodologies for the broad-based phenotyping of knockouts through a pipeline comprising 20 disease-oriented platforms. We developed new statistical methods for pipeline design and data analysis aimed at detecting reproducible phenotypes with high power. We acquired phenotype data from 449 mutant alleles, representing 320 unique genes, of which half had no previous functional annotation. We captured data from over 27,000 mice, finding that 83% of the mutant lines are phenodeviant, with 65% demonstrating pleiotropy. Surprisingly, we found significant differences in phenotype annotation according to zygosity. New phenotypes were uncovered for many genes with previously unknown function, providing a powerful basis for hypothesis generation and further investigation in diverse systems.Comment in : Genetic differential calculus. [Nat Genet. 2015] Comment in : Scaling up phenotyping studies. [Nat Biotechnol. 2015

Genetische und phänotypische Charakterisierung eines Mausmodells für erbliche Polycythämie.

Im Rahmen des Münchener ENU-Mausmutagenese-Projekts wurde durch chemische Mutagenese die dominante mutante Mauslinie MVD013 erzeugt. Die Linie wurde an Hand einer erhöhten Zahl und eines verringerten Volumens der Erythrozyten etabliert. Außerdem zeigten einzelne ältere mutante Tiere dieser Linie zusätzliche pathologische Veränderungen wie Darmtumoren und Megakolon. Ziel der Arbeit war es, Untersuchungen zur Identifizierung der ursächlichen Mutation in der Mauslinie MVD013 durchzuführen und die pathologischen Auswirkungen zu charakterisieren, um so ihre Eignung als Tiermodell für Polycythämie und Tumorerkrankungen zu evaluieren. Mittels der durchgeführten Grob- und Feinkartierungen wurde die Lage der ursächlichen Mutation auf Chromosom 5, 59,3-89,7 Mb eingegrenzt. Durch Sequenzanalyse der Kandidatengene Kit, Pdgfra und Kdr konnte keine Mutation im kodierenden Bereich dieser Gene nachgewiesen werden. Die mutante Mauslinie MVD013 wurde im Jahr 2008 im Primärscreen der Deutsche Mausklinik untersucht. Zusammen mit den zusätzlichen sekundären Untersuchungen wurde eine umfassende Phänotypbeschreibung der Mauslinie MVD013 erstellt. Die hämatologische Analyse zeigt ein der humanen Polycythämia vera entsprechendes Blutbild, mit leichter Abweichung vom typischen PV Befund in Richtung Thrombozytopenie. Die klinisch-chemischen Untersuchungen ergaben deutlich erniedrigte Glukosespiegel und Eisenkonzentrationen im Plasma der mutanten Tiere. Die Ergebnisse der Analyse zusätzlicher Parameter des Eisenstoffwechsels und die Ergebnissen des intraperitonealen Glukosetoleranztests deuten auf einen erhöhten Eisen- und Glukoseverbrauch bei mutanten Tieren hin. Anhand der Analyse der Blutgasparameter und der Erythropoetinkonzentration im Serum wurde das Vorliegen einer sekundären Erythrozytose ausgeschlossen. Die Untersuchungen der hämatopoetischen Vorläuferzellen geben einen Hinweis auf myelosuppressive Prozesse im Knochenmark der gealterten mutanten Tiere, was mit Symptomen der humanen Post-Polycythämia vera Myelofibrosis vergleichbar ist. Die mutanten Tiere der Linie MVD013 entwickeln gastrointestinale Stromatumoren in Magen und Darm sowie eine Dilatation (Megaceacum) im Bereich des Blinddarms. Somit kann die dominant mutante Mauslinie MVD013 als ein vielversprechendes Mausmodell für Polycythämia vera, gastrointestinale Stromatumoren und pathologische Veränderungen mit Störungen der Darmperistaltik dienen

Setting a limit on anthropogenic sources of atmospheric ⁸¹Kr through Atom Trap Trace Analysis

We place a 2.5% limit on the anthropogenic contribution to the modern abundance of ⁸¹Kr/Kr in the atmosphere at the 90% confidence level. Due to its simple production and transport in the terrestrial environment, ⁸¹Kr (halflife = 230,000 yr) is an ideal tracer for old water and ice with mean residence times in the range of 10^5-10^6 years. In recent years, ⁸¹Kr-dating has been made available to the earth science community thanks to the development of Atom Trap Trace Analysis (ATTA), a laser-based atom counting technique. Further upgrades and improvements to the ATTA technique now allow us to demonstrate ⁸¹Kr/Kr measurements with relative uncertainties of 1% and place this new limit on anthropogenic ⁸¹Kr. As a result of this limit, we have removed a potential systematic constraint for ⁸¹Kr-dating

Setting a limit on anthropogenic sources of atmospheric ⁸¹Kr through Atom Trap Trace Analysis

We place a 2.5% limit on the anthropogenic contribution to the modern abundance of ⁸¹Kr/Kr in the atmosphere at the 90% confidence level. Due to its simple production and transport in the terrestrial environment, ⁸¹Kr (halflife = 230,000 yr) is an ideal tracer for old water and ice with mean residence times in the range of 10^5-10^6 years. In recent years, ⁸¹Kr-dating has been made available to the earth science community thanks to the development of Atom Trap Trace Analysis (ATTA), a laser-based atom counting technique. Further upgrades and improvements to the ATTA technique now allow us to demonstrate ⁸¹Kr/Kr measurements with relative uncertainties of 1% and place this new limit on anthropogenic ⁸¹Kr. As a result of this limit, we have removed a potential systematic constraint for ⁸¹Kr-dating

A small angle neutron scattering (SANS) experiment using very cold neutrons (VCN)

This paper describes the results of SANS measurements of small samples using the very cold neutron (VCN) beam of the PF2 instrument at the Institut Laue Langevin (ILL), France. In addition to a classical SANS pinhole collimation, the experiment used a polarizing supermirror as a monochromator and a magnetic sextupole lens to focus the neutron beam in order to gain intensity and avoid any material in the neutron beam besides the sample. © 2009, Elsevier Ltd

Clinical chemistry reference intervals for C57BL/6J, C57BL/6N, and C3HeB/FeJ mice (<em>Mus musculus</em>).

Although various mouse inbred strains are widely used to investigate disease mechanisms and to establish new therapeutic strategies, sex-specific reference intervals for laboratory diagnostic analytes that are generated from large numbers of animals have been unavailable. In this retrospective study, we screened data from more than 12,000 mice phenotyped in the German Mouse Clinic from January 2006 through June 2014 and selected animals with the genetic background of C57BL/6J, C57BL/6N, or C3HeB/FeJ. In addition, we distinguished between the C57BL/6NTac substrain and C57BL/6N mice received from other vendors. The corresponding data sets of electrolytes (sodium, potassium, calcium, chloride, inorganic phosphate), lipids (cholesterol, triglyceride), and enzyme activities (ALT, AST, ALP, &alpha;-amylase) and urea, albumin, and total protein levels were analyzed. Significant effects of age and sex on these analytes were identified, and strain- or substrain- and sex-specific reference intervals for 90- to 135-d-old mice were calculated. In addition, we include an overview of the literature that reports clinical chemistry values for wild-type mice of different strains. Our results support researchers interpreting clinical chemistry values from various mouse mutants and corresponding wild-type controls based on the examined strains and substrains