Unstable DNA Repair Genes Shaped by Their Own Sequence Modifying Phenotypes

The question of whether natural selection favors genetic stability or genetic variability is a fundamental problem in evolutionary biology. Bioinformatic analyses demonstrate that selection favors genetic stability by avoiding unstable nucleotide sequences in protein encoding DNA. Yet, such unstable sequences are maintained in several DNA repair genes, thereby promoting breakdown of repair and destabilizing the genome. Several studies have therefore argued that selection favors genetic variability at the expense of stability. Here we propose a new evolutionary mechanism, with supporting bioinformatic evidence, that resolves this paradox. Combining the concepts of gene-dependent mutation biases and meiotic recombination, we argue that unstable sequences in the DNA mismatch repair (MMR) genes are maintained by their own phenotype. In particular, we predict that human MMR maintains an overrepresentation of mononucleotide repeats (monorepeats) within and around the MMR genes. In support of this hypothesis, we report a 31% excess in monorepeats in 250 kb regions surrounding the seven MMR genes compared to all other RefSeq genes (1.75 vs. 1.34%, P = 0.0047), with a particularly high content in PMS2 (2.41%, P = 0.0047) and MSH6 (2.07%, P = 0.043). Based on a mathematical model of monorepeat frequency, we argue that the proposed mechanism may suffice to explain the observed excess of repeats around MMR genes. Our findings thus indicate that unstable sequences in MMR genes are maintained through evolution by the MMR mechanism. The evolutionary paradox of genetically unstable DNA repair genes may thus be explained by an equilibrium in which the phenotype acts back on its own genotype

One of us? Negotiating multiple legal identities across the Viking diaspora

Migrations from mainland Scandinavia during the Viking age resulted in the establishment of colonies across the North Atlantic. Evidence of sustained sociocultural contact between these colonies has encouraged scholars to recognise the Viking world as a diaspora. Medieval Iceland, by way of its poets, writers, and learned men, was the locus of the memorialisation of this diaspora. Laws provide historians with a way in which to understand the creation of identity in a past society and the criteria that formed the basis of these identities. In the Viking world, where separate identities were emerging while still being connected through the diaspora, the manner in which identity was constructed and negotiated is of special interest. This paper uses Grágás, the medieval Icelandic law code, along with laws from other parts of the diaspora and Icelandic sagas to unpick how Viking diasporans negotiated identity, where they ‘belonged’, and where they were excluded

Fourteen sequence variants that associate with multiple sclerosis discovered by meta-analysis informed by genetic correlations

A meta-analysis of publicly available summary statistics on multiple sclerosis combined with three Nordic multiple sclerosis cohorts (21,079 cases, 371,198 controls) revealed seven sequence variants associating with multiple sclerosis, not reported previously. Using polygenic risk scores based on public summary statistics of variants outside the major histocompatibility complex region we quantified genetic overlap between common autoimmune diseases in Icelanders and identified disease clusters characterized by autoantibody presence/absence. As multiple sclerosis-polygenic risk scores captures the risk of primary biliary cirrhosis and vice versa (P = 1.6 x 10(-7), 4.3 x 10(-9)) we used primary biliary cirrhosis as a proxy-phenotype for multiple sclerosis, the idea being that variants conferring risk of primary biliary cirrhosis have a prior probability of conferring risk of multiple sclerosis. We tested 255 variants forming the primary biliary cirrhosis-polygenic risk score and found seven multiple sclerosis-associating variants not correlated with any previously established multiple sclerosis variants. Most of the variants discovered are close to or within immune-related genes. One is a low-frequency missense variant in TYK2, another is a missense variant in MTHFR that reduces the function of the encoded enzyme affecting methionine metabolism, reported to be dysregulated in multiple sclerosis brain.publishedVersio

SUSTAIN drilling at Surtsey volcano, Iceland, tracks hydrothermal and microbiological interactions in basalt 50 years after eruption

The 2017 Surtsey Underwater volcanic System for Thermophiles, Alteration processes and INnovative concretes (SUSTAIN) drilling project at Surtsey volcano, sponsored in part by the International Continental Scientific Drilling Program (ICDP), provides precise observations of the hydrothermal, geochemical, geomagnetic, and microbiological changes that have occurred in basaltic tephra and minor intrusions since explosive and effusive eruptions produced the oceanic island in 1963–1967. Two vertically cored boreholes, to 152 and 192 m below the surface, were drilled using filtered, UV-sterilized seawater circulating fluid to minimize microbial contamination. These cores parallel a 181 m core drilled in 1979. Introductory investigations indicate changes in material properties and whole-rock compositions over the past 38 years. A Surtsey subsurface observatory installed to 181 m in one vertical borehole holds incubation experiments that monitor in situ mineralogical and microbial alteration processes at 25–124 ∘C. A third cored borehole, inclined 55∘ in a 264∘ azimuthal direction to 354 m measured depth, provides further insights into eruption processes, including the presence of a diatreme that extends at least 100 m into the seafloor beneath the Surtur crater. The SUSTAIN project provides the first time-lapse drilling record into a very young oceanic basaltic volcano over a range of temperatures, 25–141 ∘C from 1979 to 2017, and subaerial and submarine hydrothermal fluid compositions. Rigorous procedures undertaken during the drilling operation protected the sensitive environment of the Surtsey Natural Preserve

Aconitase Regulation of Erythropoiesis Correlates with a Novel Licensing Function in Erythropoietin-Induced ERK Signaling

Erythroid development requires the action of erythropoietin (EPO) on committed progenitors to match red cell output to demand. In this process, iron acts as a critical cofactor, with iron deficiency blunting EPO-responsiveness of erythroid progenitors. Aconitase enzymes have recently been identified as possible signal integration elements that couple erythropoiesis with iron availability. In the current study, a regulatory role for aconitase during erythropoiesis was ascertained using a direct inhibitory strategy.In C57BL/6 mice, infusion of an aconitase active-site inhibitor caused a hypoplastic anemia and suppressed responsiveness to hemolytic challenge. In a murine model of polycythemia vera, aconitase inhibition rapidly normalized red cell counts, but did not perturb other lineages. In primary erythroid progenitor cultures, aconitase inhibition impaired proliferation and maturation but had no effect on viability or ATP levels. This inhibition correlated with a blockade in EPO signal transmission specifically via ERK, with preservation of JAK2-STAT5 and Akt activation. Correspondingly, a physical interaction between ERK and mitochondrial aconitase was identified and found to be sensitive to aconitase inhibition.Direct aconitase inhibition interferes with erythropoiesis in vivo and in vitro, confirming a lineage-selective regulatory role involving its enzymatic activity. This inhibition spares metabolic function but impedes EPO-induced ERK signaling and disturbs a newly identified ERK-aconitase physical interaction. We propose a model in which aconitase functions as a licensing factor in ERK-dependent proliferation and differentiation, thereby providing a regulatory input for iron in EPO-dependent erythropoiesis. Directly targeting aconitase may provide an alternative to phlebotomy in the treatment of polycythemia vera

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.Peer reviewe

Anti-resistensstrategi: skadedyr i vårkorn

Alle skadedyr kan utvikle resistens mot kjemiske midler dersom det sprøytes for ensidig og ofte. Dette temaarket gir informasjon om hvordan risikoen for resistens kan reduseres hos de viktigste skadedyrene i vårkorn (bygg, havre og hvete)

Anti-resistensstrategi: skadedyr i vårkorn

Alle skadedyr kan utvikle resistens mot kjemiske midler dersom det sprøytes for ensidig og ofte. Dette temaarket gir informasjon om hvordan risikoen for resistens kan reduseres hos de viktigste skadedyrene i vårkorn (bygg, havre og hvete).publishedVersio