Dissecting the genomic complexity underlying medulloblastoma

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group 3 and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.     

Serial translocation by means of circular intermediates underlies colour sidedness in cattle

Colour sidedness is a dominantly inherited phenotype of cattle characterized by the polarization of pigmented sectors on the flanks, snout and ear tips. It is also referred to as 'lineback' or 'witrik' (which means white back), as colour-sided animals typically display a white band along their spine. Colour sidedness is documented at least since the Middle Ages and is presently segregating in several cattle breeds around the globe, including in Belgian blue and brown Swiss. Here we report that colour sidedness is determined by a first allele on chromosome 29 (Cs(29)), which results from the translocation of a 492-kilobase chromosome 6 segment encompassing KIT to chromosome 29, and a second allele on chromosome 6 (Cs(6)), derived from the first by repatriation of fused 575-kilobase chromosome 6 and 29 sequences to the KIT locus. We provide evidence that both translocation events involved circular intermediates. This is the first example, to our knowledge, of a phenotype determined by homologous yet non-syntenic alleles that result from a novel copy-number-variant-generating mechanism.     

Reconstructing Native American population history

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call 'First American'. However, speakers of Eskimo-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America.     

Location of the sex pheromone in the American cockroach,Periplaneta americana (L.)

Zusammenfassung Das Vorkommen von Sexualpheromon wurde an dem Werbeverhalten von selektierten einzelnen Männchen getestet. Das Pheromon kommt in larvalen und adulten Insekten beiderlei Geschlechts vor, wird aber von geschlechtsreifen Weibchen in grösseren Mengen produziert. Es kommt hauptsächlich im Kopf vor und wird wahrscheinlich an Orten modifizierter Körperdecke abgesondert.     

The use of primary cultures of adult rat hepatocytes to study induction of enzymes and DNA synthesis: effect of nafenopin and electroporation

Primary cultures of adult rat hepatocytes maintained in a well-differentiated state, in a chemically defined medium containing 2% DMSO, have been utilized to study the effect of non-mutagenic hepatocarcinogens such as the peroxisome proliferator nafenopin. The parameters chosen in this in vitro system were those that paralleled the major in vivo effects of nafenopin on the liver, mainly: the proliferation of the endoplasmic reticulum and induction of cytochrome P-452, the proliferation of the peroxisome compartment and the induction of cyanide-insensitive beta-oxidation of fatty acids and the stimulation of liver growth as measured by the DNA synthetic activity of the hepatocytes. In this review, we also describe the morphology of hepatocyte cultures prepared from previously electroporated hepatocytes and the potential for the use of electroporation to introduce growth related genes into hepatocyte cells to study the mechanisms of hepatocyte growth at the molecular level. In addition we describe the formation of endoplasmic reticulum whorls in these cultures as a consequence of nafenopin treatment. 'Whorl formation' by hepatotrophic chemicals has been previously shown to occur in vivo; in this report, it is described for the first time in vitro.     

Die DNS-Synthese in Leber und Niere junger Ratten. Autoradiographische Untersuchungen mit3H-Thymidin

Summary Autoradiographic studies following a single i.p. injection of³H-thymidine were performed in liver and kidney parenchyma of new-born and young adult rats at different ages (1, 2, 4, 7, 12, 18, 24, 30, 60 and 120 days). In 1-day-old animals the tritium index (i.e. percentage of DNA synthesizing nuclei) of both organs is lower than in the rat embryo. From 1–4 days fluctuations occur, then the tritium index rises at 7 and 12 days. But now an exponential decrease is observed up to day 120. This depression and fluctuation of the tritium index probably depends on a postpartal functional transposition and especially in the liver on a structural transformation. The mean grain density in the labelled nuclei increases from 1 up to 24 days, which is likely connected with a very high amount of endogenous thymidine in new-born rats. From day 24 the mean grain density can be taken as a relative measure for the rate of DNA synthesis. The reduction in the rate of DNA synthesis from 24–120 days is explained as a consequence of the commutation from the rapid to the slow mode in cellular proliferation.

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Mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Versuche zur Erweiterung der Möglichkeiten für In-vitro-Studien an menschlichen Tumoren

Summary The paper describes some experiments designed to develop a new method for in vitro studies of human tumours. After having frozen the tissue carefully, maintaining its vitality, we cut living tissue slides of 20–30 ( thickness. Such slides may possibly be a tool for vital histology, a starter for organotypic tissue culture and a defined tissue specimen for biochemical, autoradiographical and similar studies.