Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects

Astrocytomas are the leading cause of brain cancer in humans. Because these tumours are highly infiltrative, current treatments that rely on targeting the tumour mass are often ineffective. A mouse model for astrocytoma would be a powerful tool for dissecting tumour progression and testing therapeutics. Mouse models of astrocytoma have been designed to express oncogenic proteins in astrocytes, but have had limited success due to low tumour penetrance or limited tumour progression. We present here a mouse model of astrocytomas involving mutation of two tumour-suppressor genes, Nf1 and Trp53. Humans with mutations in NF1 develop neurofibromatosis type I (NF1) and have increased risk of optic gliomas, astrocytomas and glioblastomas. The TP53 tumour suppressor is often mutated in a subset of astrocytomas that develop at a young age and progress slowly to glioblastoma (termed secondary glioblastomas, in contrast to primary glioblastomas that develop rapidly de novo). This mouse model shows a range of astrocytoma stages, from low-grade astrocytoma to glioblastoma multiforme, and may accurately model human secondary glioblastoma involving TP53 loss. This is the first reported mouse model of astrocytoma initiated by loss of tumour suppressors, rather than overexpression of transgenic oncogenes.     

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.     

Late Paleozoic magmatism in South China:Oceanic subduction or intracontinental orogeny?

A gneissic granite with an U-Pb age of 313±4 Ma was found in northeastern Fujian Province,South China.It is an S-type granite characterized by high K2O,Al2O3 and low SiO2,Na2O contents with high A/CNK ratio of 1.22 for the whole rock.Zircons with stubby morphology from the gneissic granite yield 206 Pb/238 U ages ranging from 326 to 301 Ma with a weighted average age of 313±4 Ma,and negative εHf(t) values from -8.35 to -1.74 with Hf model ages (TCDM) of 1.43 to 1.84 Ga.This S-type granite probably originated from late Paleoproterozoic crust in intracontinental orogeny.Integrated with previous results on paleogeographic reconstruction of South China,the nature of Paleozoic basins,Early Permian volcanism and U-Pb-Hf isotope of detrital zircons from the late Paleozoic to early Mesozoic sedimentary rocks,we suggest the occurrence of a late Paleozoic orogeny in the eastern Cathaysia Block,South China.This orogenic cycle includes Late Carboniferous (340-310 Ma) orogeny (compression) episode and Early Permian (287-270 Ma) post-orogenic or intraplate extension episode.Therefore,the late Paleozoic magmatism in the southeastern South China probably occurred during the intraplate orogeny rather than the arc-related process.     

Grenvillian orogeny in the Southern Cathaysia Block: Constraints from U-Pb ages and Lu-Hf isotopes in zircon from metamorphic basement

Metamorphic basement rocks in the Cathaysia Block are composed mainly of meta-sediments with different ages. New zircon U-Pb geochronological results from the meta-sedimentary rocks exposed in the Zengcheng and Hezi areas, southern Cathaysia Block, show that they consist dominantly of early Neoproterozoic （1.0-0.9 Ga） materials with minor Paleo- to Mesoproterozoic and late Neoproterozoic （0.8-0.6 Ga） components, suggesting that the detritus mostly come from a Grenvillian orogen. The youngest detrital zircon ages place a constraint on the deposition time of these sediments in Late Neoproterozoic. Zircon Hf isotopic compositions indicate that the Grenvillian zircons were derived from the reworking of Mesoproterozoic arc magmatic rocks and Paleoproterozoic continental crust, implying an arc-continent collisional setting. Single-peak age spectra and the presence of abundant euhedral Grenvillian zircons suggest that the sedimentary provenance is not far away from the sample location. Thus, the Grenvillian orogen probably preexisted along the southern margin of the Cathaysia Block, or very close to the south. Similarity in the ages of Grenvillian orogeny and the influence of the assembly of Gondwana in South China with India and East Antarctic are discussed, with suggestion that South China was more likely linked with the India-East Antarctica continents in Early Neoproterozoic rather than between western Laurentia and eastern Australia.     

Paleoproterozoic basement beneath the southern Jiangxi Province: Evidence from U-Pb ages and Lu-Hf isotopes in zircons from the Doushui lamprophyre

This paper presents geochemical analyses of a lamprophyre intruding the Caledonian Doushui granite body in Shangyou County, southern Jiangxi Province. U-Pb dating and Hf-isotope analyses are espe-cially carried out for zircons from it. Petrological and geochemical features show that the lamprophyre belongs to a high-K, weakly alkaline pyroxene-biotite lamprophyre. It is characterized by high Mg# (0.74), Ni (253 μg/g) and Cr (893 μg/g) contents, and also enriched in incompatible elements, such as REE, Rb, Sr...     

Almandine megacrysts from Yingfengling Cenozoic basalt in Leizhou Peninsula and their parental magma origin

The garnet megacrysts from Yingfengling basalts are characterized by high FeO (>20%), CaO (7.02% –8.16%) and low MgO (5.88%–10.87%). Significant composition variations are observed in these megacrysts, of which Ni, V, Sc, Co, and HREE are positively correlated with their Mg^#, and Zr, Hf, Ga, Y, Sr, Nb, Zn and LREE-MREE are negatively correlated with Mg^#. Megacryst parent magma is a highly evolved residual melt with strongl depletion in Ti, Sr, Hf, Nb and HREE. This parental magma was generated by more than 60% of crystallization fractionation of clinopyroxene, garnet, plagioclase and ilmenite from quartz tholeiitic magma. It has not erupted to the surface, but stayed at the upper mantle and formed the megacrystic cumulate. Megacrysts and their host basalt are in disequilibrium.     

A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction

Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.