Mosaic fungal individuals have the potential to evolve within a single generation

Although cells of mushroom-producing fungi typically contain paired haploid nuclei (n + n), most Armillaria gallica vegetative cells are uninucleate. As vegetative nuclei are produced by fusions of paired haploid nuclei, they are thought to be diploid (2n). Here we report finding haploid vegetative nuclei in A. gallica at multiple sites in southeastern Massachusetts, USA. Sequencing multiple clones of a single-copy gene isolated from single hyphal filaments revealed nuclear heterogeneity both among and within hyphae. Cytoplasmic bridges connected hyphae in field-collected and cultured samples, and we propose nuclear migration through bridges maintains this nuclear heterogeneity. Growth studies demonstrate among- and within-hypha phenotypic variation for growth in response to gallic acid, a plant-produced antifungal compound. The existence of both genetic and phenotypic variation within vegetative hyphae suggests that fungal individuals have the potential to evolve within a single generation in response to environmental variation over time and space

Integrated genomic characterization of endometrial carcinoma

SummaryWe performed an integrated genomic, transcriptomic, and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumors and ~25% of high-grade endometrioid tumors have extensive copy number alterations, few DNA methylation changes, low ER/PR levels, and frequent TP53 mutations. Most endometrioid tumors have few copy number alterations or TP53 mutations but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A, KRAS and novel mutations in the SWI/SNF gene ARID5B. A subset of endometrioid tumors we identified had a dramatically increased transversion mutation frequency, and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may impact post-surgical adjuvant treatment for women with aggressive tumors

The genetic landscape of high-risk neuroblastoma

Neuroblastoma is a malignancy of the developing sympathetic nervous system that often presents with widespread metastatic disease, resulting in survival rates of less than 50%1. To determine the spectrum of somatic mutation in high-risk neuroblastoma, we studied 240 cases using a combination of whole exome, genome and transcriptome sequencing as part of the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative. Here we report a low median exonic mutation frequency of 0.60 per megabase (0.48 non-silent), and remarkably few recurrently mutated genes in these tumors. Genes with significant somatic mutation frequencies included ALK (9.2% of cases), PTPN11 (2.9%), ATRX (2.5%, an additional 7.1% had focal deletions), MYCN (1.7%, a recurrent p.Pro44Leu alteration), and NRAS (0.83%). Rare, potentially pathogenic germline variants were significantly enriched in ALK, CHEK2, PINK1, and BARD1. The relative paucity of recurrent somatic mutations in neuroblastoma challenges current therapeutic strategies reliant upon frequently altered oncogenic drivers

Comprehensive molecular portraits of human breast tumours

This Article from the Cancer Genome Atlas consortium describes a multifaceted analysis of primary breast cancers in 825 people. Exome sequencing, copy number variation, DNA methylation, messenger RNA arrays, microRNA sequencing and proteomic analyses were performed and integrated to shed light on breast-cancer heterogeneity. Just three genes — TP53, PIK3CA and GATA3 — are mutated at greater than 10% frequency across all breast cancers. Many subtype-associated and novel mutations were identified, as well as two breast-cancer subgroups with specific signalling-pathway signatures. The analyses also suggest that much of the clinically observable plasticity and heterogeneity occurs within, and not across, the major subtypes of breast cancer

Multiplatform Analysis of 12 Cancer Types Reveals Molecular Classification within and across Tissues of Origin

Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies

Proterozoic Metamorphism of the Tobacco Root Mountains, Montana

Textures and mineral assemblages of metamorphic rocks of the Tobacco Root Mountains are consistent with metamorphism of all rocks during the Big Sky orogeny (1.77 Ga) at relatively high pressure (P \u3e1.0 GPa) followed by differential reequilibration on a clockwise P-T path at lower pressures (0.6–0.8 GPa). The highest pressures are documented by coarse-grained kyanite and orthopyroxene in aluminous orthoamphibolites, which require P ≥ 1.0 GPa. Other higher-pressure mineral assemblages of note include kyanite + orthoamphibole and kyanite + K-feldspar. Abundant textural evidence for partial melting in pelitic and basaltic rocks includes leucosomes, very large (several cm across) porphyroblasts of garnet, and an absence of primary (foliation-defining) muscovite. Partial to complete overprinting of the coarse-textured, high-pressure assemblages by lower-pressure assemblages and textures occurred across the Tobacco Root Mountains, especially where assisted by deformation and the availability of water. In aluminous rocks, sillimanite bundles typically replace kyanite, and garnet may be rimmed by cordierite + orthopyroxene symplectite or, in quartz-absent rocks, sapphirine + spinel + cordierite symplectite. Orthoamphibolites with partial pseudomorphs of garnet by cordierite are common. Garnet necklaces surround orthopyroxene in orthopyroxene-plagioclase gneisses, whereas orthopyroxene + plagioclase pseudomorphs of garnet occur in nearby hornblende amphibolites. These features appear to require nearly isobaric cooling at pressures near 0.8 GPa, followed by nearly isothermal decompression at temperatures near 700 °C. The resulting P-T path is believed to be the result of tectonic denudation late in the orogenic cycle. Quartz-plagioclase-garnet-hornblende amphibolites occur throughout the Tobacco Root Mountains. Near-rim mineral compositions from these rocks have been used to calculate Ts of 650–750 °C at Ps of 0.7–0.9 GPa across the terrane. There is no systematic variation in calculated P and T between units nor geographically within units; differences appear to reflect variations in thermometer closure possibly due to the availability of water during cooling. Field relations involving metamorphosed mafic dikes, as well as geochronological data from monazite and zircon, demonstrate that some rocks were first metamorphosed at high temperatures and pressures at 2.45 Ga. However, we have not i

Loss, replacement and gain of proteins at the origin of the mitochondria

Item does not contain fulltextWe review what has been inferred about the changes at the level of the proteome that accompanied the evolution of the mitochondrion from an alphaproteobacterium. We regard these changes from an alphaproteobacterial perspective: which proteins were lost during mitochondrial evolution? And, of the proteins that were lost, which ones have been replaced by other, non-orthologous proteins with a similar function? Combining literature-supported replacements with quantitative analyses of mitochondrial proteomics data we infer that most of the loss and replacements that separate current day mitochondria in mammals from alphaproteobacteria took place before the radiation of the eukaryotes. Recent analyses show that also the acquisition of new proteins to the large protein complexes of the oxidative phosphorylation and the mitochondrial ribosome occurred mainly before the divergence of the eukaryotes. These results indicate a significant number of pivotal evolutionary events between the acquisition of the endosymbiont and the radiation of the eukaryotes and therewith support an early acquisition of mitochondria in eukaryotic evolution. Technically, advancements in the reconstruction of the evolutionary trajectories of loss, replacement and gain of mitochondrial proteins depend on using profile-based homology detection methods for sequence analysis. We highlight the mitochondrial Holliday junction resolvase endonuclease, for which such methods have detected new "family members" and in which function differentiation is accompanied by the loss of catalytic residues for the original enzymatic function and the gain of a protein domain for the new function. This article is part of a Special Issue entitled: The evolutionary aspects of bioenergetic systems