Deleterious Load Research Articles

Comparative evolutionary genetics of deleterious load in sorghum and maize.

Sorghum and maize share a close evolutionary history that can be explored through comparative genomics1,2. To perform a large-scale comparison of the genomic variation between these two species, we analysed ~13 million variants identified from whole-genome resequencing of 499 sorghum lines together with 25 million variants previously identified in 1,218 maize lines. Deleterious mutations in both species were prevalent in pericentromeric regions, enriched in non-syntenic genes and present at low allele frequencies. A comparison of deleterious burden between sorghum and maize revealed that sorghum, in contrast to maize, departed from the domestication-cost hypothesis that predicts a higher deleterious burden among domesticates compared with wild lines. Additionally, sorghum and maize population genetic summary statistics were used to predict a gene deleterious index with an accuracy greater than 0.5. This research represents a key step towards understanding the evolutionary dynamics of deleterious variants in sorghum and provides a comparative genomics framework to start prioritizing these variants for removal through genome editing and breeding.

Phosphorylation of Drosophila CENP-A on serine 20 regulates protein turn-over and centromere-specific loading.

Centromeres are specialized chromosomal regions epigenetically defined by the presence of the histone H3 variant CENP-A. CENP-A is required for kinetochore formation which is essential for chromosome segregation during mitosis. Spatial restriction of CENP-A to the centromere is tightly controlled. Its overexpression results in ectopic incorporation and the formation of potentially deleterious neocentromeres in yeast, flies and in various human cancers. While the contribution of posttranslational modifications of CENP-A to these processes has been studied in yeast and mammals to some extent, very little is known about Drosophila melanogaster. Here, we show that CENP-A is phosphorylated at serine 20 (S20) by casein kinase II and that in mitotic cells, the phosphorylated form is enriched on chromatin. Importantly, our results reveal that S20 phosphorylation regulates the turn-over of prenucleosomal CENP-A by the SCFPpa-proteasome pathway and that phosphorylation promotes removal of CENP-A from ectopic but not from centromeric sites in chromatin. We provide multiple lines of evidence for a crucial role of S20 phosphorylation in controlling restricted incorporation of CENP-A into centromeric chromatin in flies. Modulation of the phosphorylation state of S20 may provide the cells with a means to fine-tune CENP-A levels in order to prevent deleterious loading to extra-centromeric sites.

The Critical Role of Development of the Transversus Abdominis in the Prevention and Treatment of Low Back Pain

The Critical Role of Development of the Transversus Abdominis in the Prevention and Treatment of Low Back Pain

Mutation bias and GC content shape antimutator invasions

Mutators represent a successful strategy in rapidly adapting asexual populations, but theory predicts their eventual extinction due to their unsustainably large deleterious load. While antimutator invasions have been documented experimentally, important discrepancies among studies remain currently unexplained. Here we show that a largely neglected factor, the mutational idiosyncrasy displayed by different mutators, can play a major role in this process. Analysing phylogenetically diverse bacteria, we find marked and systematic differences in the protein-disruptive effects of mutations caused by different mutators in species with different GC compositions. Computer simulations show that these differences can account for order-of-magnitude changes in antimutator fitness for a realistic range of parameters. Overall, our results suggest that antimutator dynamics may be highly dependent on the specific genetic, ecological and evolutionary history of a given population. This context-dependency further complicates our understanding of mutators in clinical settings, as well as their role in shaping bacterial genome size and composition.

Removal of alleles by genome editing (RAGE) against deleterious load

BackgroundIn this paper, we simulate deleterious load in an animal breeding program, and compare the efficiency of genome editing and selection for decreasing it. Deleterious variants can be identified by bioinformatics screening methods that use sequence conservation and biological prior information about protein function. However, once deleterious variants have been identified, how can they be used in breeding?ResultsWe simulated a closed animal breeding population that is subject to both natural selection against deleterious load and artificial selection for a quantitative trait representing the breeding goal. Deleterious load was polygenic and was due to either codominant or recessive variants. We compared strategies for removal of deleterious alleles by genome editing (RAGE) to selection against carriers. When deleterious variants were codominant, the best strategy for prioritizing variants was to prioritize low-frequency variants. When deleterious variants were recessive, the best strategy was to prioritize variants with an intermediate frequency. Selection against carriers was inefficient when variants were codominant, but comparable to editing one variant per sire when variants were recessive.ConclusionsGenome editing of deleterious alleles reduces deleterious load, but requires the simultaneous editing of multiple deleterious variants in the same sire to be effective when deleterious variants are recessive. In the short term, selection against carriers is a possible alternative to genome editing when variants are recessive. Our results suggest that, in the future, there is the potential to use RAGE against deleterious load in animal breeding.

Sign of selection on mutation rate modifiers depends on population size

The influence of population size (N) on natural selection acting on alleles that affect fitness has been understood for almost a century. As N declines, genetic drift overwhelms selection and alleles with direct fitness effects are rendered neutral. Often, however, alleles experience so-called indirect selection, meaning they affect not the fitness of an individual but the fitness distribution of its offspring. Some of the best-studied examples of indirect selection include alleles that modify aspects of the genetic system such as recombination and mutation rates. Here, we use analytics, simulations, and experimental populations of Saccharomyces cerevisiae to examine the influence of N on indirect selection acting on alleles that increase the genomic mutation rate (mutators). Mutators experience indirect selection via genomic associations with beneficial and deleterious mutations they generate. We show that, as N declines, indirect selection driven by linked beneficial mutations is overpowered by drift before drift can neutralize the cost of the deleterious load. As a result, mutators transition from being favored by indirect selection in large populations to being disfavored as N declines. This surprising phenomenon of sign inversion in selective effect demonstrates that indirect selection on mutators exhibits a profound and qualitatively distinct dependence on N.

A Systematic Review of Electromyography Studies in Normal Shoulders to Inform Postoperative Rehabilitation Following Rotator Cuff Repair

Study Design Systematic review. Background Electromyography (EMG) has previously been used to guide postoperative rehabilitation progression following rotator cuff repair to prevent deleterious loading of early surgical repair. Objective To review the current literature investigating EMG during rehabilitation exercises in normal shoulders, and to identify exercises that meet a cut point of 15% maximal voluntary isometric contraction (MVIC) or less and are unlikely to result in excessive loading in the early postoperative stages. Methods An electronic search of MEDLINE via Ovid, Embase, CINAHL, SPORTDiscus, PubMed, and the Cochrane Library for all years up to June 2016 was performed. Studies were selected in relation to predefined selection criteria. Pooled mean MVICs were reported and classified as low (0%-15% MVIC), low to moderate (16%-20% MVIC), moderate (21%-40% MVIC), high (41%-60% MVIC), and very high (greater than 60% MVIC). Results A search identified 2159 studies. After applying the selection criteria, 20 studies were included for quality assessment, data extraction, and data synthesis. In total, 43 exercises spanning passive range of motion, active-assisted range of motion, and strengthening exercises were evaluated. Out of 13 active-assisted exercises, 9 were identified as suitable (15% MVIC or less) to load the supraspinatus and 10 as suitable to load the infraspinatus early after surgery. All exercises were placed in a theoretical-continuum model, by which general recommendations could be made for prescription in patients post rotator cuff repair. Conclusion This review identified passive and active-assisted exercises that may be appropriate in the early stages after rotator cuff repair. J Orthop Sports Phys Ther 2017;47(12):931-944. Epub 13 Jul 2017. doi:10.2519/jospt.2017.7271.

Patient-specific chondrolabral contact mechanics in patients with acetabular dysplasia following treatment with peri-acetabular osteotomy.

Using a validated, patient-specific finite element (FE) modeling protocol, we evaluated cartilage and labrum (i.e., chondrolabral) mechanics before and after peri-acetabular osteotomy (PAO) to provide insight into the ability of this procedure to improve mechanics in dysplastic hips. Five patients with acetabular dysplasia were recruited in this case-controlled, prospective study. Models, which included anatomy for bone, cartilage, and labrum, were generated from computed tomography (CT) arthrography scans acquired before and after PAO. Cartilage and labrum contact stress and contact area were quantified overall and regionally. Load supported by the labrum, expressed as a percentage of the total hip force, was analyzed. Percent cartilage contact area increased post-operatively overall, medially, and superiorly. Peak acetabular contact stress decreased overall, laterally, anteriorly, and superiorly. Average contact stress decreased overall, laterally, anteriorly, and posteriorly. Only average contact stress on the superior labrum and peak labrum stress overall decreased. Load supported by the labrum did not change significantly. PAO was efficacious at medializing cartilage contact and reducing cartilage contact stresses, and therefore may minimize deleterious loading to focal cartilage lesions, subchondral cysts, and cartilage delaminations often observed in the lateral acetabulum of dysplastic hips. However, the excessively prominent, hypertrophied labrum of dysplastic hips remains in contact with the femoral head, which continues to load the labrum following PAO. The clinical ramifications of continued labral loading following PAO are not known. However, it is plausible that failure to reduce the load experienced by the labrum could result in end-stage hip OA following PAO.

Evolution of Mutation Rates in Rapidly Adapting Asexual Populations.

Mutator and antimutator alleles often arise and spread in both natural microbial populations and laboratory evolution experiments. The evolutionary dynamics of these mutation rate modifiers are determined by indirect selection on linked beneficial and deleterious mutations. These indirect selection pressures have been the focus of much earlier theoretical and empirical work, but we still have a limited analytical understanding of how the interplay between hitchhiking and deleterious load influences the fates of modifier alleles. Our understanding is particularly limited when clonal interference is common, which is the regime of primary interest in laboratory microbial evolution experiments. Here, we calculate the fixation probability of a mutator or antimutator allele in a rapidly adapting asexual population, and we show how this quantity depends on the population size, the beneficial and deleterious mutation rates, and the strength of a typical driver mutation. In the absence of deleterious mutations, we find that clonal interference enhances the fixation probability of mutators, even as they provide a diminishing benefit to the overall rate of adaptation. When deleterious mutations are included, natural selection pushes the population toward a stable mutation rate that can be suboptimal for the adaptation of the population as a whole. The approach to this stable mutation rate is not necessarily monotonic: even in the absence of epistasis, selection can favor mutator and antimutator alleles that "overshoot" the stable mutation rate by substantial amounts.

On the Trail of Linked Selection

Distinguishing the relative roles of positive and negative selection along with demographic history in shaping genetic diversity has been a decades-long endeavor. Understanding the forces structuring genetic variation informs us not only about the factors maintaining diversity but also about the fundamental evolutionary parameters that influence natural populations, including the rate and strength of positive selection, the deleterious genetic load experienced by populations, and the factors driving genome evolution. Most attempts at modeling demography, positive selection, or negative selection typically do so by ignoring the contribution of the other forces. Because multiple forces are acting simultaneously, these inferences likely overestimate the role of single evolutionary forces and can lead to biased interpretations. In this issue, Elyashiv et al. [1] make important advances towards addressing this problem by presenting a novel approach to simultaneously estimate the parameters of positive and negative selection based on the spatial patterns of neutral genetic variation and apply this method to Drosophila.

Recombination Rate Variation, Hitchhiking, and Demographic History Shape Deleterious Load in Poplar.

Deleterious alleles are expected to be purged by purifying selection or maintained at low frequency. However, many additional evolutionary forces may shape the pattern of deleterious mutations across the genome and among populations, including selection, hitchhiking, recombination, and demographic history. We used exome capture data to estimate the genome-wide distribution of deleterious alleles across natural populations of the model tree black cottonwood (Populus trichocarpa). Although deleterious alleles were on average present at low frequency suggesting purifying selection, they were preferentially enriched both within genomic regions of low-recombination and in regions showing evidence of positive selection. The demographic history of this species also appeared to play a role in the distribution of deleterious alleles among populations, with peripheral populations having higher rates of deleterious homozygosity. This be due to less efficient selection arising from smaller effective population sizes at the edges of the range, and possibly also due to recent bottlenecks associated with postglacial recolonization. Finally, correlations between deleterious homozygosity and plant growth suggest a significant effect of deleterious load on fitness. Our results show that both genomic context and historical demography play a role in shaping the distribution of deleterious alleles across the genome and range of P. trichocarpa.

Immediate Loading of Dental Implants - A Case Study

The ability to achieve predictable results in oral implantology depends on indepth knowledge of all factors affecting bone healing, as well as on implant characteristics and the mechanical forces involved in immediate loading. The success of the immediate loading protocol relies on three main factors: (1) primary stability, which limits micromotion of the implant, (2) secondary biologic stability, resulting in osteogenesis in the peri-implant area, and (3) the control of bone resorption caused by deleterious loading forces that lead to implant instability during healing. Activated platelets play a crucial role in peri-implant healing and the use of Plasma Rich in Growth Factors (PRGF) in association with immediate implant placement could be a viable therapeutic option for the reabilitation of postextraction sockets. In our case-study, the implants and the abutments were welded with a titanium bar in order to provide predictable fixation and immobility of implants in early stages of bone healing. The implants have been properly integrated at both the bone and gingiva levels allowing the patient to resume both esthetic and masticatory functions from the very day the implants are inserted.

Evidence for deleterious hepatitis C virus quasispecies mutation loads that differentiate the response patterns in IFN-based antiviral therapy.

Viral quasispecies (QS) have long been considered to affect the efficiency of hepatitis C virus (HCV) antiviral therapy, but a correlation between QS diversity and treatment outcomes has not been established conclusively. We previously measured HCV QS diversity by genome-wide quantification of high-resolution mutation load in HCV genotype 1a patients achieving a sustained virological response (1a/SVR) or a null response (1a/null). The current study extended this work into HCV 1a patients experiencing relapse (1a/relapse, n = 19) and genotype 2b patients with SVR (2b/SVR, n = 10). The mean mutation load per patient in 2b/SVR and 1a/relapse was similar, respectively, to 1a/SVR (517.6 ± 174.3 vs 524 ± 278.8 mutations, P = 0.95) and 1a/null (829.2 ± 282.8 vs 805.6 ± 270.7 mutations, P = 0.78). Notably, a deleterious mutation load, as indicated by the percentage of non-synonymous mutations, was highest in 2b/SVR (33.2 ± 8.5%) as compared with 1a/SVR (23.6 ± 7.8%, P = 0.002), 1a/null (18.2 ± 5.1%, P = 1.9 × 10(-7)) or 1a/relapse (17.8 ± 5.3%, P = 1.8) × 10(-6). In the 1a/relapse group, continuous virus evolution was observed with excessive accumulation of a deleterious load (17.8 ± 5.3% vs 35.4 ± 12.9%, P = 3.5 × 10(-6)), supporting the functionality of Muller's ratchet in a treatment-induced population bottleneck. Taken together, the magnitude of HCV mutation load, particularly the deleterious mutation load, provides an evolutionary explanation for the emergence of multiple response patterns as well as an overall high SVR rate in HCV genotype 2 patients. Augmentation of Muller's ratchet represents a potential strategy to reduce or even eliminate viral relapse in HCV antiviral therapy.

Electric Load Transient Recognition With a Cluster Weighted Modeling Method

This paper considers the use of sequential cluster weighted modeling (SCWM) for electric load transient recognition and energy consumption prediction that are promising for isolating the deleterious load transients from delicate renewable sources. Two computational processes co-exist in the SCWM scheme. In the training process, we propose a cluster weighted normalized least mean squares modification of the expectation maximization method to address the singular matrix inversion problem in updating the local model parameters. For the prediction process, we propose a sequential version of the CWM prediction that not only improves the real time performance of load transient recognition, but also resolves online overlapping transients. Other real time transient processing issues are also addressed. The methods are demonstrated using benchmark electric load transients.

Plant chemistry underlies herbivore‐mediated inbreeding depression in nature

The cost of inbreeding (inbreeding depression, ID) is an important variable in the maintenance of reproductive variation. Ecological interactions such as herbivory could modulate this cost, provided that defence traits harbour deleterious mutations and herbivores are responsible for differences in fitness. In the field, we manipulated the presence of herbivores on experimentally inbred and outcrossed plants of Solanum carolinense (horsenettle) for three years. Damage was greater on inbred plants, and ID for growth and fitness was significantly greater under herbivory. Inbreeding reduced phenolic expression both qualitatively (phytochemical diversity) and quantitatively, indicating deleterious load at loci related to the biosynthesis of defence compounds. Our results indicate that inbreeding effects on plant-herbivore interactions are mediated by changes to functional plant metabolites, suggesting that variation in inbreeding could be a predictor of defence trait variation. The magnitude of herbivore-mediated, ecological ID indicates that herbivores could maintain outcrossing mating systems in nature.

Inbreeding depression in self-incompatible North-American Arabidopsis lyrata: disentangling genomic and S-locus-specific genetic load

Newly formed selfing lineages may express recessive genetic load and suffer inbreeding depression. This can have a genome-wide genetic basis, or be due to loci linked to genes under balancing selection. Understanding the genetic architecture of inbreeding depression is important in the context of the maintenance of self-incompatibility and understanding the evolutionary dynamics of S-alleles. We addressed this using North-American subspecies of Arabidopsis lyrata. This species is normally self-incompatible and outcrossing, but some populations have undergone a transition to selfing. The goals of this study were to: (1) quantify the strength of inbreeding depression in North-American populations of A. lyrata; and (2) disentangle the relative contribution of S-linked genetic load compared with overall inbreeding depression. We enforced selfing in self-incompatible plants with known S-locus genotype by treatment with CO(2), and compared the performance of selfed vs outcrossed progeny. We found significant inbreeding depression for germination rate (δ=0.33), survival rate to 4 weeks (δ=0.45) and early growth (δ=0.07), but not for flowering rate. For two out of four S-alleles in our design, we detected significant S-linked load reflected by an under-representation of S-locus homozygotes in selfed progeny. The presence or absence of S-linked load could not be explained by the dominance level of S-alleles. Instead, the random nature of the mutation process may explain differences in the recessive deleterious load among lineages.

A MATE-Family Efflux Pump Rescues the Escherichia coli 8-Oxoguanine-Repair-Deficient Mutator Phenotype and Protects Against H2O2 Killing

Hypermutation may accelerate bacterial evolution in the short-term. In the long-term, however, hypermutators (cells with an increased rate of mutation) can be expected to be at a disadvantage due to the accumulation of deleterious mutations. Therefore, in theory, hypermutators are doomed to extinction unless they compensate the elevated mutational burden (deleterious load). Different mechanisms capable of restoring a low mutation rate to hypermutators have been proposed. By choosing an 8-oxoguanine-repair-deficient (GO-deficient) Escherichia coli strain as a hypermutator model, we investigated the existence of genes able to rescue the hypermutable phenotype by multicopy suppression. Using an in vivo-generated mini-MudII4042 genomic library and a mutator screen, we obtained chromosomal fragments that decrease the rate of mutation in a mutT-deficient strain. Analysis of a selected clone showed that the expression of NorM is responsible for the decreased mutation rate in 8-oxoguanine-repair-deficient (mutT, mutY, and mutM mutY) strains. NorM is a member of the multidrug and toxin extrusion (MATE) family of efflux pumps whose role in E. coli cell physiology remains unknown. Our results indicate that NorM may act as a GO-system backup decreasing AT to CG and GC to TA transversions. In addition, the ability of NorM to reduce the level of intracellular reactive oxygen species (ROS) in a GO-deficient strain and protect the cell from oxidative stress, including protein carbonylation, suggests that it can extrude specific molecules—byproducts of bacterial metabolism—that oxidize the guanine present in both DNA and nucleotide pools. Altogether, our results indicate that NorM protects the cell from specific ROS when the GO system cannot cope with the damage.

Lethal Mutagenesis of Bacteria

Lethal mutagenesis, the killing of a microbial pathogen with a chemical mutagen, is a potential broad-spectrum antiviral treatment. It operates by raising the genomic mutation rate to the point that the deleterious load causes the population to decline. Its use has been limited to RNA viruses because of their high intrinsic mutation rates. Microbes with DNA genomes, which include many viruses and bacteria, have not been considered for this type of treatment because their low intrinsic mutation rates seem difficult to elevate enough to cause extinction. Surprisingly, models of lethal mutagenesis indicate that bacteria may be candidates for lethal mutagenesis. In contrast to viruses, bacteria reproduce by binary fission, and this property ensures their extinction if subjected to a mutation rate >0.69 deleterious mutations per generation. The extinction threshold is further lowered when bacteria die from environmental causes, such as washout or host clearance. In practice, mutagenesis can require many generations before extinction is achieved, allowing the bacterial population to grow to large absolute numbers before the load of deleterious mutations causes the decline. Therefore, if effective treatment requires rapid population decline, mutation rates >>0.69 may be necessary to achieve treatment success. Implications for the treatment of bacteria with mutagens, for the evolution of mutator strains in bacterial populations, and also for the evolution of mutation rate in cancer are discussed.

Non-invasive assessment of fluid responsiveness

Only fifty percent of critically ill patients have still some cardiac preload reserve and respond to volume expansion by a significant increase cardiac output. This emphasizes the need for predictive factors of fluid responsiveness to avoid ineffective or deleterious volume loading. Since clinical evaluation is of poor value, sophisticated parameters have been proposed to help the caregiver in the decision making process concerning volume expansion. Markers of cardiac preload have been shown to lack sensitivity and specificity for predicting volume responsiveness. Minimally invasive haemodynamic devices provide the clinician with dynamic markers of volume responsiveness. In mechanically ventilated patients, the magnitude of respiratory changes in stroke volume or its surrogates has been proposed to detect volume responsiveness. Accordingly, respiratory variations of arterial pulse pressure, of arterial pulse contour-derived stroke volume, of Doppler aortic blood velocity or flow, have been reported as exc...

Insuffisance du premier rayon

First bone ray insufficiency refers to a pressure defect on the first metatarsal head; it should be considered as a syndrome related to several diagnoses, not only at the level of the first ray but also at the level of the second ray, and even of the intermetatarsal spaces. The most frequent cause is an inadequate length of the first bone ray. Diagnosis is sometimes difficult due to multiple clinical presentations, but standard or electronic podometry can confirm the diagnosis by ascertaining a deleterious load transfer to median rays. Routine X-ray allows visualising the metatarsus and the relationships between the metatarsal bones according to their respective length, which is the pathophysiological basis of this affection. After the diagnosis is established and the static disorder is identified, medical instructions are proposed to the patient, such as shoe optimisation, lifestyle measures, rehabilitation, and above all plantar orthesis fitting. In case of treatment failure or inefficacy despite good compliance, surgery may be considered. Depending on the existence or absence of a first ray shift in the foot axis (metatarsus varus), the surgeon will act only on the metatarsus in order to restore harmonious shape, or on the first ray, or on both.