A central focus of population genetics has been examining the contribution of selective and neutral processes in shaping patterns of intraspecies diversity. In terms of selection specifically, ...surveys of higher organisms have shown considerable variation in the relative contributions of background selection and genetic hitchhiking in shaping the distribution of polymorphisms, although these analyses have rarely been extended to bacteria and viruses. Here, we study the evolution of a ubiquitous, viral pathogen, human cytomegalovirus (HCMV), by analysing the relationship among intraspecies diversity, interspecies divergence and rates of recombination. We show that there is a strong correlation between diversity and divergence, consistent with expectations of neutral evolution. However, after correcting for divergence, there remains a significant correlation between intraspecies diversity and recombination rates, with additional analyses suggesting that this correlation is largely due to the effects of background selection. In addition, a small number of loci, centred on long noncoding RNAs, also show evidence of selective sweeps. These data suggest that HCMV evolution is dominated by neutral mechanisms as well as background selection, expanding our understanding of linked selection to a novel class of organisms.
Congenital cytomegalovirus (cCMV) is the leading infectious cause of neurologic defects in newborns with particularly severe sequelae in the setting of primary CMV infection in the first trimester of ...pregnancy. The majority of cCMV cases worldwide occur after non-primary infection in CMV-seropositive women; yet the extent to which pre-existing natural CMV-specific immunity protects against CMV reinfection or reactivation during pregnancy remains ill-defined. We previously reported on a novel nonhuman primate model of cCMV in rhesus macaques where 100% placental transmission and 83% fetal loss were seen in CD4+ T lymphocyte-depleted rhesus CMV (RhCMV)-seronegative dams after primary RhCMV infection. To investigate the protective effect of preconception maternal immunity, we performed reinfection studies in CD4+ T lymphocyte-depleted RhCMV-seropositive dams inoculated in late first / early second trimester gestation with RhCMV strains 180.92 (n = 2), or RhCMV UCD52 and FL-RhCMVΔRh13.1/SIVgag, a wild-type-like RhCMV clone with SIVgag inserted as an immunological marker, administered separately (n = 3). An early transient increase in circulating monocytes followed by boosting of the pre-existing RhCMV-specific CD8+ T lymphocyte and antibody response was observed in the reinfected dams but not in control CD4+ T lymphocyte-depleted dams. Emergence of SIV Gag-specific CD8+ T lymphocyte responses in macaques inoculated with the FL-RhCMVΔRh13.1/SIVgag virus confirmed reinfection. Placental transmission was detected in only one of five reinfected dams and there were no adverse fetal sequelae. Viral whole genome, short-read, deep sequencing analysis confirmed transmission of both reinfection RhCMV strains across the placenta with ~30% corresponding to FL-RhCMVΔRh13.1/SIVgag and ~70% to RhCMV UCD52, consistent with the mixed human CMV infections reported in infants with cCMV. Our data showing reduced placental transmission and absence of fetal loss after non-primary as opposed to primary infection in CD4+ T lymphocyte-depleted dams indicates that preconception maternal CMV-specific CD8+ T lymphocyte and/or humoral immunity can protect against cCMV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The characterization of the distribution of mutational effects is a key goal in evolutionary biology. Recently developed deep-sequencing approaches allow for accurate and simultaneous estimation of ...the fitness effects of hundreds of engineered mutations by monitoring their relative abundance across time points in a single bulk competition. Naturally, the achievable resolution of the estimated fitness effects depends on the specific experimental setup, the organism and type of mutations studied, and the sequencing technology utilized, among other factors. By means of analytical approximations and simulations, we provide guidelines for optimizing time-sampled deep-sequencing bulk competition experiments, focusing on the number of mutants, the sequencing depth, and the number of sampled time points. Our analytical results show that sampling more time points together with extending the duration of the experiment improves the achievable precision disproportionately compared with increasing the sequencing depth or reducing the number of competing mutants. Even if the duration of the experiment is fixed, sampling more time points and clustering these at the beginning and the end of the experiment increase experimental power and allow for efficient and precise assessment of the entire range of selection coefficients. Finally, we provide a formula for calculating the 95%-confidence interval for the measurement error estimate, which we implement as an interactive web tool. This allows for quantification of the maximum expected a priori precision of the experimental setup, as well as for a statistical threshold for determining deviations from neutrality for specific selection coefficient estimates.
Mutations are the source of evolutionary variation. The interactions of multiple mutations can have important effects on fitness and evolutionary trajectories. We have recently described the ...distribution of fitness effects of all single mutations for a nine-amino-acid region of yeast Hsp90 (Hsp82) implicated in substrate binding. Here, we report and discuss the distribution of intragenic epistatic effects within this region in seven Hsp90 point mutant backgrounds of neutral to slightly deleterious effect, resulting in an analysis of more than 1,000 double mutants. We find negative epistasis between substitutions to be common, and positive epistasis to be rare--resulting in a pattern that indicates a drastic change in the distribution of fitness effects one step away from the wild type. This can be well explained by a concave relationship between phenotype and genotype (i.e., a concave shape of the local fitness landscape), suggesting mutational robustness intrinsic to the local sequence space. Structural analyses indicate that, in this region, epistatic effects are most pronounced when a solvent-inaccessible position is involved in the interaction. In contrast, all 18 observations of positive epistasis involved at least one mutation at a solvent-exposed position. By combining the analysis of evolutionary and biophysical properties of an epistatic landscape, these results contribute to a more detailed understanding of the complexity of protein evolution.
The Scanning Habitable Environments with Raman and Luminescence for Organics
and Chemicals (SHERLOC) is a robotic arm-mounted instrument on NASA’s Perseverance
rover. SHERLOC has two primary ...boresights. The Spectroscopy boresight generates
spatially resolved chemical maps using fluorescence and Raman spectroscopy coupled to
microscopic images (10.1 μm/pixel). The second boresight is a Wide Angle Topographic
Sensor for Operations and eNgineering (WATSON); a copy of the Mars Science Laboratory
(MSL) Mars Hand Lens Imager (MAHLI) that obtains color images from microscopic
scales (∼13 μm/pixel) to infinity. SHERLOC Spectroscopy focuses a 40 μs pulsed deep UV
neon-copper laser (248.6 nm), to a ∼100 μm spot on a target at a working distance of ∼48
mm. Fluorescence emissions from organics, and Raman scattered photons from organics
and minerals, are spectrally resolved with a single diffractive grating spectrograph with a
spectral range of 250 to ∼370 nm. Because the fluorescence and Raman regions are naturally
separated with deep UV excitation (<250 nm), the Raman region ∼ 800 – 4000 cm−1
(250 to 273 nm) and the fluorescence region (274 to ∼370 nm) are acquired simultaneously
without time gating or additional mechanisms. SHERLOC science begins by using an Autofocus
Context Imager (ACI) to obtain target focus and acquire 10.1 μm/pixel greyscale
images. Chemical maps of organic and mineral signatures are acquired by the orchestration
of an internal scanning mirror that moves the focused laser spot across discrete points on
the target surface where spectra are captured on the spectrometer detector. ACI images and
chemical maps (< 100 μm/mapping pixel) will enable the first Mars in situ view of the spatial
distribution and interaction between organics, minerals, and chemicals important to the
assessment of potential biogenicity (containing CHNOPS). Single robotic arm placement
chemical maps can cover areas up to 7x7 mm in area and, with the < 10 min acquisition
time per map, larger mosaics are possible with arm movements. This microscopic view of
the organic geochemistry of a target at the Perseverance field site, when combined with
the other instruments, such as Mastcam-Z, PIXL, and SuperCam, will enable unprecedented
analysis of geological materials for both scientific research and determination of which samples
to collect and cache for Mars sample return.
We here propose an analysis pipeline for inferring the distribution of fitness effects (DFE) from either patient-sampled or experimentally-evolved viral populations, that explicitly accounts for ...non-Wright-Fisher and non-equilibrium population dynamics inherent to pathogens. We examine the performance of this approach via extensive power and performance analyses, and highlight two illustrative applications - one from an experimentally-passaged RNA virus, and the other from a clinically-sampled DNA virus. Finally, we discuss how such DFE inference may shed light on major research questions in virus evolution, ranging from a quantification of the population genetic processes governing genome size, to the role of Hill-Robertson interference in dictating adaptive outcomes, to the potential design of novel therapeutic approaches to eradicate within-patient viral populations via induced mutational meltdown.
The recurrent fixation of newly arising, beneficial mutations in a species reduces levels of linked neutral variability. Models positing frequent weakly beneficial substitutions or, alternatively, ...rare, strongly selected substitutions predict similar average effects on linked neutral variability, if the product of the rate and strength of selection is held constant. We propose an approximate Bayesian (ABC) polymorphism-based estimator that can be used to distinguish between these models, and apply it to multi-locus data from Drosophila melanogaster. We investigate the extent to which inference about the strength of selection is sensitive to assumptions about the underlying distributions of the rates of substitution and recombination, the strength of selection, heterogeneity in mutation rate, as well as the population's demographic history. We show that assuming fixed values of selection parameters in estimation leads to overestimates of the strength of selection and underestimates of the rate. We estimate parameters for an African population of D. melanogaster (ŝ approximately 2E-03, ) and compare these to previous estimates. Finally, we show that surveying larger genomic regions is expected to lend much more discriminatory power to the approach. It will thus be of great interest to apply this method to emerging whole-genome polymorphism data sets in many taxa.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Cancer nanotechnologies possess immense potential as therapeutic and diagnostic treatment modalities and have undergone significant and rapid advancement in recent years. With this ...emergence, the complexities of data standards in the field are on the rise. Data sharing and reanalysis is essential to more fully utilize this complex, interdisciplinary information to answer research questions, promote the technologies, optimize use of funding, and maximize the return on scientific investments. In order to support this, various data-sharing portals and repositories have been developed which not only provide searchable nanomaterial characterization data, but also provide access to standardized protocols for synthesis and characterization of nanomaterials as well as cutting-edge publications. The National Cancer Institute’s (NCI) caNanoLab is a dedicated repository for all aspects pertaining to cancer-related nanotechnology data. The searchable database provides a unique opportunity for data mining and the use of artificial intelligence and machine learning, which aims to be an essential arm of future research studies, potentially speeding the design and optimization of next-generation therapies. It also provides an opportunity to track the latest trends and patterns in nanomedicine research. This manuscript provides the first look at such trends extracted from caNanoLab and compares these to similar metrics from the NCI's Nanotechnology Characterization Laboratory, a laboratory providing preclinical characterization of cancer nanotechnologies to researchers around the globe. Together, these analyses provide insight into the emerging interests of the research community and rise of promising nanoparticle technologies.
Antiviral drug resistance is a matter of great clinical importance that, historically, has been investigated mostly from a virological perspective. Although the proximate mechanisms of resistance can ...be readily uncovered using these methods, larger evolutionary trends often remain elusive. Recent interest by population geneticists in studies of antiviral resistance has spurred new metrics for evaluating mutation and recombination rates, demographic histories of transmission and compartmentalization, and selective forces incurred during viral adaptation to antiviral drug treatment. We present up-to-date summaries on antiviral resistance for a range of drugs and viral types, and review recent advances for studying their evolutionary histories. We conclude that information imparted by demographic and selective histories, as revealed through population genomic inference, is integral to assessing the evolution of antiviral resistance as it pertains to human health.
The role of adaptation in molecular evolution has been contentious for decades. Here, we shed light on the adaptive potential in Saccharomyces cerevisiae by presenting systematic fitness measurements ...for all possible point mutations in a region of Hsp90 under four environmental conditions. Under elevated salinity, we observe numerous beneficial mutations with growth advantages up to 7% relative to the wild type. All of these beneficial mutations were observed to be associated with high costs of adaptation. We thus demonstrate that an essential protein can harbor adaptive potential upon an environmental challenge, and report a remarkable fit of the data to a version of Fisher's geometric model that focuses on the fitness trade-offs between mutations in different environments.
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