Many forces influence genetic variation across the genome including mutation, recombination, selection, and demography. Increased mutation and recombination both lead to increases in genetic ...diversity in a region-specific manner, while complex demographic patterns shape patterns of diversity on a more global scale. While these processes act across the entire genome, the X chromosome is particularly interesting because it contains several distinct regions that are subject to different combinations and strengths of these forces: the pseudoautosomal regions (PARs) and the X-transposed region (XTR). The X chromosome thus can serve as a unique model for studying how genetic and demographic forces act in different contexts to shape patterns of observed variation. We therefore sought to explore diversity, divergence, and linkage disequilibrium in each region of the X chromosome using genomic data from 26 human populations. Across populations, we find that both diversity and substitution rate are consistently elevated in PAR1 and the XTR compared to the rest of the X chromosome. In contrast, linkage disequilibrium is lowest in PAR1, consistent with the high recombination rate in this region, and highest in the region of the X chromosome that does not recombine in males. However, linkage disequilibrium in the XTR is intermediate between PAR1 and the autosomes, and much lower than the non-recombining X. Finally, in addition to these global patterns, we also observed variation in ratios of X versus autosomal diversity consistent with population-specific evolutionary history as well. While our results were generally consistent with previous work, two unexpected observations emerged. First, our results suggest that the XTR does not behave like the rest of the recombining X and may need to be evaluated separately in future studies. Second, the different regions of the X chromosome appear to exhibit unique patterns of linked selection across different human populations. Together, our results highlight profound regional differences across the X chromosome, simultaneously making it an ideal system for exploring the action of evolutionary forces as well as necessitating its careful consideration and treatment in genomic analyses.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Phylogenetic inference in bacterial genomics is fundamental to understanding problems such as population history, antimicrobial resistance, and transmission dynamics. The field has been plagued by an ...apparent state of contradiction since the distorting effects of recombination on phylogeny were discovered more than a decade ago. Researchers persist with detailed phylogenetic analyses while simultaneously acknowledging that recombination seriously misleads inference of population dynamics and selection. Here we resolve this paradox by showing that phylogenetic tree topologies based on whole genomes robustly reconstruct the clonal frame topology but that branch lengths are badly skewed. Surprisingly, removing recombining sites can exacerbate branch length distortion caused by recombination.
Phylogenetic tree reconstruction is a popular approach for understanding the relatedness of bacteria in a population from differences in their genome sequences. However, bacteria frequently exchange regions of their genomes by a process called homologous recombination, which violates a fundamental assumption of phylogenetic methods. Since many researchers continue to use phylogenetics for recombining bacteria, it is important to understand how recombination affects the conclusions drawn from these analyses. We find that whole-genome sequences afford great accuracy in reconstructing evolutionary relationships despite concerns surrounding the presence of recombination, but the branch lengths of the phylogenetic tree are indeed badly distorted. Surprisingly, methods to reduce the impact of recombination on branch lengths can exacerbate the problem.
The cause of the end-Cretaceous mass extinction is vigorously debated, owing to the occurrence of a very large bolide impact and flood basalt volcanism near the boundary. Disentangling their relative ...importance is complicated by uncertainty regarding kill mechanisms and the relative timing of volcanogenic outgassing, impact, and extinction. We used carbon cycle modeling and paleotemperature records to constrain the timing of volcanogenic outgassing. We found support for major outgassing beginning and ending distinctly before the impact, with only the impact coinciding with mass extinction and biologically amplified carbon cycle change. Our models show that these extinction-related carbon cycle changes would have allowed the ocean to absorb massive amounts of carbon dioxide, thus limiting the global warming otherwise expected from postextinction volcanism.
Background Exposure to green vegetation has been linked to positive health, but the pathophysiological processes affected by exposure to vegetation remain unclear. To study the relationship between ...greenness and cardiovascular disease, we examined the association between residential greenness and biomarkers of cardiovascular injury and disease risk in susceptible individuals. Methods and Results In this cross-sectional study of 408 individuals recruited from a preventive cardiology clinic, we measured biomarkers of cardiovascular injury and risk in participant blood and urine. We estimated greenness from satellite-derived normalized difference vegetation index ( NDVI ) in zones with radii of 250 m and 1 km surrounding the participants' residences. We used generalized estimating equations to examine associations between greenness and cardiovascular disease biomarkers. We adjusted for residential clustering, demographic, clinical, and environmental variables. In fully adjusted models, contemporaneous NDVI within 250 m of participant residence was inversely associated with urinary levels of epinephrine (-6.9%; 95% confidence interval, -11.5, -2.0/0.1 NDVI ) and F2-isoprostane (-9.0%; 95% confidence interval, -15.1, -2.5/0.1 NDVI ). We found stronger associations between NDVI and urinary epinephrine in women, those not on β-blockers, and those who had not previously experienced a myocardial infarction. Of the 15 subtypes of circulating angiogenic cells examined, 11 were inversely associated (8.0-15.6% decrease/0.1 NDVI ), whereas 2 were positively associated (37.6-45.8% increase/0.1 NDVI ) with contemporaneous NDVI . Conclusions Independent of age, sex, race, smoking status, neighborhood deprivation, statin use, and roadway exposure, residential greenness is associated with lower levels of sympathetic activation, reduced oxidative stress, and higher angiogenic capacity.
Coronavirus Disease-19 (COVID-19), caused by the coronavirus SARS-CoV-2, was initially recognized in Wuhan, China and subsequently spread to all continents. The disease primarily affects the lower ...respiratory system, but may involve other organs and systems. Histopathologic evaluation of tissue from affected patients is crucial for diagnostic purposes, but also for advancing our understanding of the disease. For that reason, we developed immunohistochemical (IHC) and in situ hybridization (ISH) assays for detection of the. virus. A total of eight autopsy lungs, one placenta, and ten kidney biopsies from COVID-19 patients were stained with a panel of commercially available antibodies for IHC and commercially available RNA probes for ISH. Similarly, autopsy lungs, placentas and renal biopsies from non-COVID-19 patients were stained with the same antibodies and probes. All eight lungs and the placenta from COVID-19 patients stained positive by IHC and ISH, while the kidney biopsies stained negative by both methodologies. As expected, all specimens from non-COVID-19 patients were IHC and ISH negative. These two assays represent a sensitive and specific method for detecting the virus in tissue samples. We provide the protocols and the list of commercially available antibodies and probes for these assays, so they can be readily implemented in pathology laboratories and medical examiner offices for diagnostic and research purposes.
Detailed protocols for immunohistochemical and in situ hybridization assays for the detection of SARS-CoV-2 are provide so they can be readily implemented in pathology laboratories and medical examiner offices for diagnostic and research purposes. These assays were found to represent a sensitive and specific method for detecting the virus in tissue samples.
Bacteria can exchange and acquire new genetic material from other organisms directly and via the environment. This process, known as bacterial recombination, has a strong impact on the evolution of ...bacteria, for example, leading to the spread of antibiotic resistance across clades and species, and to the avoidance of clonal interference. Recombination hinders phylogenetic and transmission inference because it creates patterns of substitutions (homoplasies) inconsistent with the hypothesis of a single evolutionary tree. Bacterial recombination is typically modeled as statistically akin to gene conversion in eukaryotes,
, using the coalescent with gene conversion (CGC). However, this model can be very computationally demanding as it needs to account for the correlations of evolutionary histories of even distant loci. So, with the increasing popularity of whole genome sequencing, the need has emerged for a faster approach to model and simulate bacterial genome evolution. We present a new model that approximates the coalescent with gene conversion: the bacterial sequential Markov coalescent (BSMC). Our approach is based on a similar idea to the sequential Markov coalescent (SMC)-an approximation of the coalescent with crossover recombination. However, bacterial recombination poses hurdles to a sequential Markov approximation, as it leads to strong correlations and linkage disequilibrium across very distant sites in the genome. Our BSMC overcomes these difficulties, and shows a considerable reduction in computational demand compared to the exact CGC, and very similar patterns in simulated data. We implemented our BSMC model within new simulation software FastSimBac. In addition to the decreased computational demand compared to previous bacterial genome evolution simulators, FastSimBac provides more general options for evolutionary scenarios, allowing population structure with migration, speciation, population size changes, and recombination hotspots. FastSimBac is available from https://bitbucket.org/nicofmay/fastsimbac, and is distributed as open source under the terms of the GNU General Public License. Lastly, we use the BSMC within an Approximate Bayesian Computation (ABC) inference scheme, and suggest that parameters simulated under the exact CGC can correctly be recovered, further showcasing the accuracy of the BSMC. With this ABC we infer recombination rate, mutation rate, and recombination tract length of
from a whole genome alignment.
Finerenone reduced risk of cardiorenal outcomes in patients with CKD and type 2 diabetes in the FIDELIO-DKD trial. We report incidences and risk factors for hyperkalemia with finerenone and placebo ...in FIDELIO-DKD.
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safety analysis defined hyperkalemia as ≥mild or ≥moderate based on serum potassium concentrations of >5.5 or >6.0 mmol/L, respectively, assessed at all regular visits. Cumulative incidences of hyperkalemia were based on the Aalen-Johansen estimator using death as competing risk. A multivariate Cox proportional hazards model identified significant independent predictors of hyperkalemia. Restricted cubic splines assessed relationships between short-term post-baseline changes in serum potassium or eGFR and subsequent hyperkalemia risk. During the study, serum potassium levels guided drug dosing. Patients in either group who experienced ≥mild hyperkalemia had the study drug withheld until serum potassium was ≤5.0 mmol/L; then the drug was restarted at the 10 mg daily dose. Placebo-treated patients underwent sham treatment interruption and downtitration.
Over 2.6 years' median follow-up, 597 of 2785 (21.4%) and 256 of 2775 (9.2%) patients treated with finerenone and placebo, respectively, experienced treatment-emergent ≥mild hyperkalemia; 126 of 2802 (4.5%) and 38 of 2796 (1.4%) patients, respectively, experienced moderate hyperkalemia. Independent risk factors for ≥mild hyperkalemia were higher serum potassium, lower eGFR, increased urine albumin-creatinine ratio, younger age, female sex,
-blocker use, and finerenone assignment. Diuretic or sodium-glucose cotransporter-2 inhibitor use reduced risk. In both groups, short-term increases in serum potassium and decreases in eGFR were associated with subsequent hyperkalemia. At month 4, the magnitude of increased hyperkalemia risk for any change from baseline was smaller with finerenone than with placebo.
Finerenone was independently associated with hyperkalemia. However, routine potassium monitoring and hyperkalemia management strategies employed in FIDELIO-DKD minimized the impact of hyperkalemia, providing a basis for clinical use of finerenone.
Whole-genome sequencing offers new insights into the evolution of bacterial pathogens and the etiology of bacterial disease. Staphylococcus aureus is a major cause of bacteria-associated mortality ...and invasive disease and is carried asymptomatically by 27% of adults. Eighty percent of bacteremias match the carried strain. However, the role of evolutionary change in the pathogen during the progression from carriage to disease is incompletely understood. Here we use high-throughput genome sequencing to discover the genetic changes that accompany the transition from nasal carriage to fatal bloodstream infection in an individual colonized with methicillin-sensitive S. aureus. We found a single, cohesive population exhibiting a repertoire of 30 single-nucleotide polymorphisms and four insertion/deletion variants. Mutations accumulated at a steady rate over a 13-mo period, except for a cluster of mutations preceding the transition to disease. Although bloodstream bacteria differed by just eight mutations from the original nasally carried bacteria, half of those mutations caused truncation of proteins, including a premature stop codon in an AraC-family transcriptional regulator that has been implicated in pathogenicity. Comparison with evolution in two asymptomatic carriers supported the conclusion that clusters of protein-truncating mutations are highly unusual. Our results demonstrate that bacterial diversity in vivo is limited but nonetheless detectable by whole-genome sequencing, enabling the study of evolutionary dynamics within the host. Regulatory or structural changes that occur during carriage may be functionally important for pathogenesis; therefore identifying those changes is a crucial step in understanding the biological causes of invasive bacterial disease.
We present two-feldspar thermometry and diffusion chronometry from sanidine, orthopyroxene and quartz from multiple samples of the Bishop Tuff, California, to constrain the temperature stratification ...within the pre-eruptive magma body and the timescales of magma mixing prior to its evacuation. Two-feldspar thermometry yields estimates that agree well with previous Fe–Ti oxide thermometry and gives a ~80 °C temperature difference between the earlier- and later-erupted regions of the magma chamber. Using the thermometry results, we model diffusion of Ti in quartz, and Ba and Sr in sanidine as well as Fe–Mg interdiffusion in orthopyroxene to yield timescales for the formation of overgrowth rims on these crystal phases. Diffusion profiles of Ti in quartz and Fe–Mg in orthopyroxene both yield timescales of <150 years for the formation of overgrowth rims. In contrast, both Ba and Sr diffusion in sanidine yield nominal timescales 1–2 orders of magnitude longer than these two methods. The main cause for this discrepancy is inferred to be an incorrect assumption for the initial profile shape for Ba and Sr diffusion modelling (i.e. growth zoning exists). Utilising the divergent diffusion behaviour of Ba and Sr, we place constraints on the initial width of the interface and can refine our initial conditions considerably, bringing Ba and Sr data into alignment, and yielding timescales closer to 500 years, the majority of which are then within uncertainty of timescales modelled from Ti diffusion in quartz. Care must be thus taken when using Ba in sanidine geospeedometry in evolved magmatic systems where no other phases or elements are available for comparative diffusion profiling. Our diffusion modelling reveals piecemeal rejuvenation of the lower parts of the Bishop Tuff magma chamber at least 500 years prior to eruption. Timescales from our mineral profiling imply either that diffusion coefficients currently used are uncertain by 1–2 orders of magnitude, or that the minerals concerned did not experience a common history, despite being extracted from the same single pumice clasts. Introduction of the magma initiating crystallisation of the contrasting rims on sanidine, quartz, orthopyroxene and zircon was prolonged, and may be a marker of other processes that initiated the Bishop Tuff eruption rather than the trigger itself.
The magmatic systems that give rise to voluminous crystal-poor rhyolite magma bodies can be considered to operate on two contrasting timescales: Those governed by longer-term processes by which a ...magma acquires its chemical and isotopic characteristics (e.g., fractional crystallisation and assimilation), and those operating at shorter timescales during the physical accumulation of the melt-dominant magma body that finally erupts. We explore the compositional and textural relationships between amphibole and orthopyroxene crystals from the 25.4 ka, 530 km
3
(magma) Oruanui eruption products (Taupo volcano, New Zealand) to investigate how processes related to the physical assembly of the pre-eruptive magma body are represented in the crystal record. Over 90 % of orthopyroxenes from the volumetrically dominant high-SiO
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(>74 wt%) rhyolite pumices record textural evidence for a significant disequilibrium event (partial dissolution ± resorption of cores and interiors) prior to the growth of 40–500 μm thick rim zones. This dissolution/regrowth history of orthopyroxene is recorded in the chemistry of co-crystallising amphiboles as a prominent inflection in the concentrations of Mn and Zn, two elements notably enriched in orthopyroxene relative to amphibole. Textural and chemical features, linked with in situ thermobarometric estimates, indicate that a major decompression event preceded the formation of the melt-dominant body. The decompression event is inferred to represent the extraction of large volumes of melt plus crystals from the Oruanui crystal mush/source zone at pressures of 140–300 MPa (~6–12 km depth). Orthopyroxene underwent partial dissolution during ascent before reestablishing in the melt-dominant magma body at pressures of 90–140 MPa (~3.5–6 km). We model Fe–Mg diffusion across the core-rim boundaries along the crystallographic
a
or
b
-axes to constrain the timing of this decompression event, which marked establishment of the melt-dominant magma body. Maximum modelled ages indicate that this event did not begin until ~1,600 years before eruption, consistent with constraints from zircon model-age spectra. Once extraction began, it underwent runaway acceleration with a peak extraction age of ~230 years, followed by an apparent period of stasis of ~60 years prior to eruption. The rapidity of the extraction and accumulation processes implies the involvement of a dynamic driving force which, in the rifted continental arc setting of the Taupo Volcanic Zone, seems likely to be represented by magma-assisted extensional tectonic processes.
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