RNase L reprograms translation by widespread mRNA turnover escaped by antiviral mRNAs, bioRxiv, 2018-12-05
SUMMARYIn response to foreign and endogenous double-stranded RNA (dsRNA), protein kinase R (PKR) and ribonuclease L (RNase L) reprogram translation in mammalian cells. PKR inhibits translation initiation through eIF2α phosphorylation, which triggers stress granule (SG) formation and promotes translation of stress responsive mRNAs. The mechanisms of RNase L-driven translation repression, its contribution to SG assembly, and its regulation of dsRNA stress-induced mRNAs are unknown. We demonstrate that RNase L drives translational shut-off in response to dsRNA by promoting widespread turnover of mRNAs. This alters stress granule assembly and reprograms translation by only allowing for the translation of mRNAs resistant to RNase L degradation, including numerous antiviral mRNAs such as IFN-β. Individual cells differentially activate dsRNA responses revealing variation that can affect cellular outcomes. This identifies bulk mRNA degradation and the resistance of antiviral mRNAs as the mechanism by which RNaseL reprograms translation in response to dsRNA.
biorxiv immunology 0-100-users 2018Geographic variation and bias in polygenic scores of complex diseases and traits in Finland, bioRxiv, 2018-12-04
AbstractPolygenic scores (PS) are becoming a useful tool to identify individuals with high genetic risk for complex diseases and several projects are currently testing their utility for translational applications. It is also tempting to use PS to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how population genetic properties of the training and target samples affect the geographic distribution of PS. Here, we evaluate geographic differences, and related biases, of PS in Finland with geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PS for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waits-hip ratio (WHR), body-mass index (BMI) and height, but not for Crohn’s disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PS and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulation of geographic differences for CAD, WHR, BMI and height, suggesting bias arising from population genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PS are for small biases even within relatively homogenous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PS is essential for translational applications of PS.
biorxiv genetics 100-200-users 2018Insights from Bacillus anthracis strains isolated from permafrost in the tundra zone of Russia, bioRxiv, 2018-12-04
This article describes Bacillus anthracis strains isolated during an outbreak of anthrax on the Yamal Peninsula in the summer of 2016 and independently in Yakutia in 2015. A common feature of these strains is their conservation in permafrost, from which they were extracted either due to the thawing of permafrost (Yamal strains) or as the result of paleontological excavations (Yakut strains). All strains isolated on the Yamal share an identical genotype belonging to lineage B.Br.001002, pointing to a common source of infection in a territory over 250 km in length. In contrast, during the excavations in Yakutia, three genetically different strains were recovered from a single pit. One strain belongs to B.Br.001002, as the Yamal strains. Despite the remoteness of Yamal from Yakutia, whole genome sequence analysis showed that the B.Br.001002 strains are very closely related. The two other strains contribute to two different branches of A.Br.008011, one of the remarkable polytomies described so far in B. anthracis population. The geographic distribution of the strains belonging to this polytomy is suggesting that this polytomy emerged in the thirteenth century, in combination with the constitution of a unified Mongol empire extending from China to Eastern Europe. We propose an evolutionary model for B. anthracis recent evolution in which the B lineage spread throughout Eurasia and was subsequently replaced by the A lineage except in some geographically isolated areas.
biorxiv microbiology 100-200-users 2018Talent Identification at the limits of Peer Review an analysis of the EMBO Postdoctoral Fellowships Selection Process, bioRxiv, 2018-12-04
Scientific peer review is still the most common system for fund allocation despite having been shown in multiple instances to lack accuracy in identifying the most meritorious applications among high quality ones. This study evaluates two aspects of the selection process of the top- ranked applicants to the EMBO Long-Term Fellowship program in 2007. First, the accuracy of the system is evaluated by comparing the level of career progression of the candidates in 2017 with the original award decisions made in 2007. The second aspect, explores the relationship of career progression with indicators derived from the information available to evaluators at the time of application. The results obtained suggest that the peer review system is not substantially better than random selection in identifying the best candidates once an initial pre-selection of the most promising ones is performed. Not only that, the analysis of the indicators studied, some of which have not been analyzed in detail in the past, suggests that among other potential sources of uncertainty, the information available at the time of application is not sufficiently predictive of career progression. As previously described, however, we find differences in career progression between men and women. We propose a new mixed model of fellowship evaluation in which peer review is used to select high quality applications, and random allocation of funds is subsequently used to award fellowships among these top ranked candidates.
biorxiv scientific-communication-and-education 500+-users 2018The skull of StW 573, a 3.67 Ma Australopithecus skeleton from Sterkfontein Caves, South Africa, bioRxiv, 2018-12-04
Here we present the first full anatomical description of the 3.67 million-year-old Australopithecus skull StW 573 that was recovered with its skeleton from the Sterkfontein Member 2 breccia in the Silberberg Grotto. Analysis demonstrates that it is most similar in multiple key morphological characters to a group of fossils from Sterkfontein Member 4 and Makapansgat that are here distinguished morphologically as A. prometheus. This taxon contrasts with another group of fossils from those sites assigned to A. africanus. The anatomical reasons for why these groupings should not be lumped together (as is frequently done for the South African fossils) are discussed in detail. In support of this classification, we also present for the first time a palate (StW 576 from Sterkfontein Member 4) newly reconstructed by RJC, which has a uniquely complete adult dentition of an A. africanus. The StW 573 skull also has certain similarities with other earlier Australopithecus fossils in East Africa, A. afarensis and A. anamensis, which are discussed. One of its most interesting features is a pattern of very heavy anterior dental wear unlike that found in A. africanus but resembling that found in A. anamensis at 4.17 Ma. While StW 573 is the only hominid fossil in Sterkfontein Member 2, we conclude that competitive exclusion probably accounts for the synchronous and sympatric presence of two species of Australopithecus in the younger deposits at Makapansgat and Sterkfontein Member 4. Because the StW 573 skull is associated with a near-complete skeleton that is also described for the first time in this special issue, we are now able to use this individual to improve our understanding of more fragmentary finds in the South African fossil record of Australopithecus.
biorxiv paleontology 100-200-users 2018Ultra-deep, long-read nanopore sequencing of mock microbial community standards, bioRxiv, 2018-12-04
Background Long sequencing reads are information-rich aiding de novo assembly and reference mapping, and consequently have great potential for the study of microbial communities. However, the best approaches for analysis of long-read metagenomic data are unknown. Additionally, rigorous evaluation of bioinformatics tools is hindered by a lack of long-read data from validated samples with known composition.Methods We sequenced two commercially-available mock communities containing ten microbial species (ZymoBIOMICS Microbial Community Standards) with Oxford Nanopore GridION and PromethION. Isolates from the same mock community were sequenced individually with Illumina HiSeq.Data We generated 14 and 16 Gbp from GridION flowcells and 146 and 148 Gbp from PromethION flowcells for the even and odd communities respectively. Read length N50 was 5.3 Kbp and 5.2 Kbp for the even and log community, respectively. Basecalls and corresponding signal data are made available (4.2 TB in total). Results Alignment to Illumina-sequenced isolates demonstrated the expected microbial species at anticipated abundances, with the limit of detection for the lowest abundance species below 50 cells (GridION). De novo assembly of metagenomes recovered long contiguous sequences without the need for pre-processing techniques such as binning.Conclusions We present ultra-deep, long-read nanopore datasets from a well-defined mock community. These datasets will be useful for those developing bioinformatics methods for long-read metagenomics and for the validation and comparison of current laboratory and software pipelines.
biorxiv bioinformatics 100-200-users 2018