Distribution and habitat segregation on different spatial scales among diploid, tetraploid and hexaploid cytotypes of Senecio carniolicus (Asteraceae) in the Eastern Alps

The spatial distribution of cytotypes can provide valuable insights into evolutionary patterns of polyploid complexes. In a previous study the macro-scale distribution of the three main cytotypes in Senecio carniolicus (Asteraceae) within the Eastern Alps was characterized. Employing a roughly 12-fold extended sampling, the present study focuses on unravelling patterns of cytotype distribution on the meso- and microscale and on correlating those with ecological properties of the growing sites. DAPI flow cytometry of dried samples was used to determine DNA ploidy level in 5033 individuals from 100 populations spread over the entire Eastern Alpine distribution area of S. carniolicus. Descriptors of microhabitats as well as spatial data were recorded in the field, and analysed with a mixed-effects ANOVA. Extensive variation in DNA ploidy levels (2x, 3x, 4x, 5x, 6x, 7x, 8x, 9x) was detected. Of the main cytotypes, diploids and hexaploids were widespread and had strongly overlapping distributions resulting in the frequent occurrence of cytotype mixtures (half of the investigated populations), whereas tetraploids were disjunctly distributed and occurred in the south-west and the east of the species' distribution area. In spite of the frequent co-occurrence of cytotypes, only 1 % of the samples belonged to secondary cytotypes (3x, 5x, 7x, 8x, 9x). Diploids, tetraploids and hexaploids were altitudinally segregated, but with broad overlap. Similarly, highly significant differences in vegetation and rock cover as well as microhabitat exposure were found between the main cytotypes. Senecio carniolicus shows a remarkable diversity of cytotypes. The distribution of the three main cytotypes (2x, 4x, 6x) has been shaped by Pleistocene glaciations to different extents. Whereas tetraploids are nearly entirely restricted to refugia, hexaploids colonized areas that were extensively glaciated. Diploid and hexaploid individuals often co-occur in mixed populations, where they are spatially and ecologically segregated at both the meso-scale (altitudinal differentiation, exposure of the growing site) and the micro-scale (cover of vegetation and bare rock). With regard to the ecological parameters investigated, the tetraploid cytotype occupies an intermediate position. The rareness of secondary cytotypes suggests the presence of strong pre- or post-zygotic mating barriers

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Cancer LncRNA Census reveals evidence for deep functional conservation of long noncoding RNAs in tumorigenesis.

Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis

Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Spontaneous Binding of Molecular Oxygen at the Q_<i>o</i>‑Site of the <i>bc</i>₁ Complex Could Stimulate Superoxide Formation

A key part of the respiratory and photosynthetic pathways is the <i>bc</i>₁ protein complex embedded in the inner membrane of mitochondria and the plasma membrane of photosynthetic bacteria. The protein complex pumps protons across the membrane to maintain an electrostatic potential, which is in turn used to drive ATP synthesis. This molecular machinery, however, is suspected to be a source of superoxide, which is toxic to the cell, even in minuscular quantities, and believed to be a factor in aging. Through molecular dynamics simulations, we investigate here the migration of molecular oxygen in the <i>bc</i>₁ complex in order to identify possible reaction sites that could lead to superoxide formation. It is found, in particular, that oxygen penetrates spontaneously the Q_<i>o</i> binding site of the <i>bc</i>₁ complex in the presence of an intermediate semiquinone radical, thus making the Q_<i>o</i>-site a strong candidate for being a center of superoxide production

Mutations at the Q_o Site of the Cytochrome <i>b</i><i>c</i>₁ Complex Strongly Affect Oxygen Binding

The homodimeric <i>bc</i>₁ protein complex is embedded in membranes of mitochondria and photosynthetic bacteria, where it transports protons across the membrane to maintain an electrostatic potential used to drive ATP synthesis as part of the respiratory or photosynthetic pathways. The reaction cycle of the <i>bc</i>₁ complex is driven by series of redox processes involving substrate molecules from the membrane, but occasional side reactions between an intermediate semiquinone substrate and molecular oxygen are suspected to be a source of toxic superoxide, which is believed to be a factor in aging. The present investigation employs molecular dynamics simulations to study the effect of mutations in the Q_o binding sites of the <i>bc</i>₁ complex on the ability of oxygen molecules to migrate to and bind at various locations within the complex. It is found that the mutations strongly affect the ability of oxygen to bind at the Q_o sites, and moreover, different behavior of the two monomers of the <i>bc</i>₁ complex is observed. The conformational differences at the Q_o sites of the two monomers are studied in detail and discussed. The anionic form of semiquinone was identified as leading to the greatest opportunity for side reactions with oxygen