Neutral Phenotypes Research Articles

The impact of different alignment strategies on bone cuts for neutral knee phenotypes in total knee arthroplasty

PurposeThe purpose of this study was to simulate and visualise the influence of the alignment strategy on bone resection in neutral knee phenotypes. It was hypothesised that different amounts of bone resection would be required depending on the alignment strategy chosen. The hypothesis was that by visualising the corresponding bone cuts, it would be possible to assess which of the different alignment strategies required the least change to the soft tissues for the chosen phenotype but still ensured acceptable component alignment and could, therefore, be considered the most ideal alignment strategy.MethodsSimulations of the different alignment strategies (mechanical, anatomical, restricted kinematic and unrestricted kinematic) regarding their bone resections were performed on four common exemplary neutral knee phenotypes. NEUHKA0° VARFMA 90° VALTMA90°, NEUHKA0° NEUFMA 93° NEUTMA87°, NEUHKA0° VALFMA 96° NEUTMA87° and NEUHKA0° VALFMA 99° VARTMA84°. The phenotype system used categorises knees based on overall limb alignment (i.e. hip knee angle) but also considers joint line obliquity (i.e. TKA and FMA) and has been used globally since its introduction in 2019. These simulations are based on long leg weightbearing radiographs. It is assumed that a change of 1° in the alignment of the joint line corresponds to correspond to 1 mm of distal condyle offset.ResultsIn the most common neutral phenotype NEUHKA0° NEUFMA 93° NEUTMA87°, with a prevalence of 30%, bone cuts remain below 4 mm regardless of alignment strategy. The greatest changes in the obliquity of the joint line can be expected for the mechanical alignment of the phenotype NEUHKA0° VALFMA 99° VARTMA84° where the medial tibia is raised by 6 mm and the lateral femur is shifted distally by 9 mm. In contrast, the NEUHKA0° VARFMA 90° VALTMA90° phenotype requires no change in joint line obliquity if the mechanical alignment strategy is used.ConclusionIllustrations of alignment strategies help the treating surgeon to estimate the postoperative joint line obliquity. When considering the alignment strategy, it seems reasonable to prefer a strategy where the joint line obliquity is changed as little as possible. Although for the most common neutral knee phenotype the choice of alignment strategy seems to be of negligible importance, in general, even for neutral phenotypes, large differences in bone cuts can be observed depending on the choice of alignment strategy.

Mechanically aligned total knee arthroplasty with the extension-first technique does not equally restore neutral knee alignment in all preoperative knee phenotypes

PurposeThe aim of this study was to determine the change in the long leg axis according to the preoperative knee phenotype using the mechanically aligned extension-first technique in total knee arthroplasty. The hypothesis of this study was that the knee phenotype would have an impact on the postoperative leg axis.MethodsThis was a retrospective comparative study comprising 224 whole-leg radiographs of 112 patients. The leg axes of the pre- and postoperative radiographs were measured and categorized into three preoperative limb phenotypes (based on the hip-knee-ankle angle [HKA]) according to Hirschmann et al. (varus—HKA < 178.5°, neutral—HKA 178.5°–181.5°, and valgus—HKA > 181.5°). Additionally, femoral phenotypes (based on the femoral mechanical angle [FMA], i.e., the mechanical medial distal femoral angle [mMDFA], as well as the tibial phenotypes [based on the tibial mechanical angle, i.e., the medial proximal tibial angle (MPTA)] was calculated. The change in the long leg axis was analyzed and compared with the preoperative limb phenotype.ResultsSignificantly more patients with preoperative varus alignment shifted to neutral alignment (46.3%, n = 31) than did patients with preoperative valgus alignment (38.9%; n = 14). Moreover, 43.3% of patients (n = 29) with the varus phenotype remained in a varus alignment, compared with the 58.3% of patients with preoperative valgus phenotype (n = 21) remaining in valgus alignment. These findings were similar for both females (p < 0.001) and males (p = 0.015).ConclusionUsing an extension-first mechanically aligned surgical technique, varus phenotypes predominantly result in neutral leg axes or remain varus, neutral phenotypes remain neutral, and valgus phenotypes remain valgus or change to neutral phenotypes. This study showed that preoperative knee phenotypes in valgus knees influence this technique more strongly than estimated in previous investigations, which is in line with modern alignment philosophies for TKA.Level of evidenceLevel IV, retrospective comparative study.

Echocardiography Study of Hypertrophic Cardiomyopathy Phenotypes

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disorder with a heterogeneous phenotype. Historically, only obstructive and nonobstructive forms have been described. Improvements in imaging techniques have led to elaborative description of various new phenotypes, although there are limited epidemiological data regarding these phenotypes from within our population. Aims and Objectives: •To identify HCM patients from a cohort of cardiomyopathy patients. •To describe their demographic profile and mode of presentation based on the presenting symptoms. •To subclassify the selected HCM population into various phenotypes based on echocardiography. Results: There were 233 patients of HCM in this study. The mean age of the patients was 53 ± 14.5 years with male preponderance (70%). Thirty-six percent patients were asymptomatic, 37% mildly symptomatic (in class I-II), and 27% severely symptomatic (in class III-IV). Patients were classified into six phenotypes consisting of five classically described phenotypes and one atypical phenotype. Reverse curvature phenotype was most prevalent (49%) and symptomatic phenotype with 19.3% having significant resting left ventricular outflow tract (LVOT) obstruction. Other phenotypes were 19% apical mid, 11% neutral, 6% sigmoid, and 4% atypical. Male: female ratio for reverse curvature phenotype was 3:1, apical (mid) phenotype 2.4:1, and both apical and neutral phenotypes 2:1. Sigmoid phenotype had female-to-male ratio of 2.5:1. Conclusion: HCM patients require phenotype specific approach for complete assessment. Transthoracic echocardiography with myocardial contrast plays a pivotal role in identifying morphological phenotypes, effects on cardiac remodeling and hemodynamics which consequently influence mode of presentation. Reverse curvature, apical mid, and sigmoid phenotypes are comparatively more symptomatic, have larger left atrial size and segment thickness compared to less symptomatic apical and neutral phenotypes. Symptom status of the patient seems to be dependent on age, septal contour, severity of LVOT obstruction, left atrial volume, and maximal segment thickness.

Many roads lead to Rome: Neutral phenotypes in microorganisms.

John Bonner pointed out that microorganisms differ in several ways, some of which may reflect neutral phenotypic evolution. For making his case, Bonner referred to interspecies differences and morphological traits. Here we consider intraspecies differences and physiological traits. As a case-study, we examine the production of an extracellular cyclic 3 ,5 monophosphate phosphodiesterase in the cellular slime mold Dictyostelium discoideum. Temporal profiles of phosphodiesterase activity differ significantly between wild-type strains. From that we argue that the inference drawn initially from studies on a single wild-type, namely that the profile displayed by it pointed to an adaptive role, was mistaken. We generalize the conclusion to suggest that physiological differences exhibited by microorganisms of the same species may, but need not, reflect adaptations to different environments. Rather, the differences could be related to the fact that microorganisms live in groups whose composition can vary between homogeneous (clonal) and heterogeneous (polyclonal). More than one physiological profile is consistent with the normal development of the group in a given environment; the alternatives are neutral. When studying microbial physiology and behavior, it is expected that the observations are made on a clonal population; genetic (and so phenotypic) heterogeneity is carefully guarded against. As the example from D. discoideum shows, an unintended consequence of overlooking phenotypic heterogeneity is that one can fall into the trap of accepting a seemingly plausible, but possibly erroneous, adaptive explanation for a "normal" wild-type phenotype.

Inherent forms and the evolution of evolution.

John Bonner presented a provocative conjecture that the means by which organisms evolve has itself evolved. The elements of his postulated nonuniformitarianism in the essay under discussion-the emergence of sex, the enhanced selection pressures on larger multicellular forms-center on a presumed close mapping of genotypic to phenotypic change. A different view emerges from delving into earlier work of Bonner's in which he proposed the concept of "neutral phenotypes" and "neutral morphologies" allied to D'Arcy Thompson's analysis of physical determinants of form and studied the conditional elicitation of intrinsic organizational properties of cell aggregates in social amoebae. By comparing the shared and disparate mechanistic bases of morphogenesis and developmental outcomes in the embryos of metazoans (animals), closely related nonmetazoan holozoans, more distantly related dictyostelids, and very distantly related volvocine algae, I conclude, in agreement with Bonner's earlier proposals, that understanding the evolution of multicellular evolution requires knowledge of the inherent forms of diversifying lineages, and that the relevant causative factors extend beyond genes and adaptation to the physics of materials.

Multiple infection of cells changes the dynamics of basic viral evolutionary processes.

The infection of cells by multiple copies of a given virus can impact viral evolution in a variety of ways, yet some of the most basic evolutionary dynamics remain underexplored. Using computational models, we investigate how infection multiplicity affects the fixation probability of mutants, the rate of mutant generation, and the timing of mutant invasion. An important insight from these models is that for neutral and disadvantageous phenotypes, rare mutants initially enjoy a fitness advantage in the presence of multiple infection of cells. This arises because multiple infection allows the rare mutant to enter more target cells and to spread faster, while it does not accelerate the spread of the resident wild‐type virus. The rare mutant population can increase by entry into both uninfected and wild‐type‐infected cells, while the established wild‐type population can initially only grow through entry into uninfected cells. Following this initial advantageous phase, the dynamics are governed by drift or negative selection, respectively, and a higher multiplicity reduces the chances that mutants fix in the population. Hence, while increased infection multiplicity promotes the presence of neutral and disadvantageous mutants in the short‐term, it makes it less likely in the longer term. We show how these theoretical insights can be useful for the interpretation of experimental data on virus evolution at low and high multiplicities. The dynamics explored here provide a basis for the investigation of more complex viral evolutionary processes, including recombination, reassortment, as well as complementary/inhibitory interactions.

Phylogenetic Quantification of Intratumor Heterogeneity

As sequencing efforts continue to reveal the extent of the intratumor heterogeneity (ITH) present in human cancers, the importance of evolutionary studies attempting to trace its etiology has increased. Sequencing multiple samples or tumor regions from the same patient has become affordable and is an effective way of tracing these evolutionary pathways, understanding selection, and detecting clonal expansions in ways impractical with single samples alone. In this article, we discuss and show the benefits of such multisample studies. We describe how multiple samples can guide tree inference through accurate phasing of germline variants and copy-number profiles. We show their relevance in detecting clonal expansions and deriving summary statistics quantifying the overall degree of ITH, and discuss how the relationship of metastatic clades might give us insight into the dominant mode of cancer progression. We further outline how multisample studies might help us better understand selective processes acting on cancer genomes and help to detect neutral evolution and mutator phenotypes.

How discordant morphological and molecular evolution among microorganisms can revise our notions of biodiversity on Earth.

Microscopy has revealed tremendous diversity of bacterial and eukaryotic forms. Recent molecular analyses show discordance in estimates of biodiversity between morphological and molecular analyses. Moreover, phylogenetic analyses of the diversity of microbial forms reveal evidence of convergence at scales as deep as interdomain: morphologies shared between bacteria and eukaryotes. Here, we highlight examples of such discordance, focusing on exemplary lineages such as testate amoebae, ciliates, and cyanobacteria. These have long histories of morphological study, enabling deeper analyses on both the molecular and morphological sides. We discuss examples in two main categories: (i) morphologically identical (or highly similar) individuals that are genetically distinct and (ii) morphologically distinct individuals that are genetically the same. We argue that hypotheses about discordance can be tested using the concept of neutral morphologies, or more broadly neutral phenotypes, as a null hypothesis.

Evolution in subdivided plant populations: concepts, recent advances and future directions

Research into the evolution of subdivided plant populations has long involved the study of phenotypic variation across plant geographic ranges and the genetic details underlying that variation. Genetic polymorphism at different marker loci has also allowed us to infer the long- and short-term histories of gene flow within and among populations, including range expansions and colonization-extinction dynamics. However, the advent of affordable genome-wide sequences for large numbers of individuals is opening up new possibilities for the study of subdivided populations. In this review, we consider what the new tools and technologies may allow us to do. In particular, we encourage researchers to look beyond the description of variation and to use genomic tools to address new hypotheses, or old ones afresh. Because subdivided plant populations are complex structures, we caution researchers away from adopting simplistic interpretations of their data, and to consider the patterns they observe in terms of the population genetic processes that have given rise to them; here, the genealogical framework of the coalescent will continue to be conceptually and analytically useful.

The role of balanced training and testing data sets for binary classifiers in bioinformatics.

Training and testing of conventional machine learning models on binary classification problems depend on the proportions of the two outcomes in the relevant data sets. This may be especially important in practical terms when real-world applications of the classifier are either highly imbalanced or occur in unknown proportions. Intuitively, it may seem sensible to train machine learning models on data similar to the target data in terms of proportions of the two binary outcomes. However, we show that this is not the case using the example of prediction of deleterious and neutral phenotypes of human missense mutations in human genome data, for which the proportion of the binary outcome is unknown. Our results indicate that using balanced training data (50% neutral and 50% deleterious) results in the highest balanced accuracy (the average of True Positive Rate and True Negative Rate), Matthews correlation coefficient, and area under ROC curves, no matter what the proportions of the two phenotypes are in the testing data. Besides balancing the data by undersampling the majority class, other techniques in machine learning include oversampling the minority class, interpolating minority-class data points and various penalties for misclassifying the minority class. However, these techniques are not commonly used in either the missense phenotype prediction problem or in the prediction of disordered residues in proteins, where the imbalance problem is substantial. The appropriate approach depends on the amount of available data and the specific problem at hand.

From nature to the laboratory: the impact of founder effects on adaptation

Most founding events entail a reduction in population size, which in turn leads to genetic drift effects that can deplete alleles. Besides reducing neutral genetic variability, founder effects can in principle shift additive genetic variance for phenotypes that underlie fitness. This could then lead to different rates of adaptation among populations that have undergone a population size bottleneck as well as an environmental change, even when these populations have a common evolutionary history. Thus, theory suggests that there should be an association between observable genetic variability for both neutral markers and phenotypes related to fitness. Here, we test this scenario by monitoring the early evolutionary dynamics of six laboratory foundations derived from founders taken from the same source natural population of Drosophila subobscura. Each foundation was in turn three-fold replicated. During their first few generations, these six foundations showed an abrupt increase in their genetic differentiation, within and between foundations. The eighteen populations that were monitored also differed in their patterns of phenotypic adaptation according to their immediately ancestral founding sample. Differences in early genetic variability and in effective population size were found to predict differences in the rate of adaptation during the first 21 generations of laboratory evolution. We show that evolution in a novel environment is strongly contingent not only on the initial composition of a newly founded population but also on the stochastic changes that occur during the first generations of colonization. Such effects make laboratory populations poor guides to the evolutionary genetic properties of their ancestral wild populations.

Craniofacial differences between skeletal Class II and skeletal Class I malocclusions according to vertical classification

The aim of this study was to determine morphological differences among Class II, division 1 (Class II,1) subjects with different rotation models according to mandibular plane inclination and to compare these with normal subjects. The study consisted of 132 subjects (99 Class II,1 and 33 Class I control group). The Class II,1 group included subjects who had ANB (point A-nasion-point B) angles greater than 4° with an overjet equal to or greater than 5 mm. Based on the SN/Go-Gn (cranial base anterior length/gonion-gnathion) angle, subjects were divided into three different rotation models as hypodivergent, normodivergent and hyperdivergent. Variance analysis (ANOVA) was used to assess the presence of differences between groups (p 0.05). Although the ramus (Cd-Go) was significantly shorter in the Class II,1 hyperdivergent group (p < 0.05), the hypodivergent group had similar ramus heights compared with controls. Class II groups showed a similar increase in the ANB angle in spite of a different vertical rotation type. This study concludes that future Class II studies should divide subjects into subgroups according to hypodivergent, neutral and hyperdivergent phenotypes.

Genetic and phenotypic diversity of autochthonous cider yeasts in a cellar from Asturias

This paper analyses yeast diversity and dynamics during the production of Asturian cider. Yeasts were isolated from apple juice and at different stages of fermentation in a cellar in Villaviciosa during two Asturian cider-apple harvests. The species identified by ITS-RFLP corresponded to Hanseniaspora valbyensis, Hanseniaspora uvarum, Metschnikowia pulcherrima, Pichia guilliermondii, Candida parapsilosis, Saccharomyces cerevisiae and Saccharomyces bayanus/Saccharomyces pastorianus/Saccharomyces kudriavzevii/Saccharomyces mikatae. The species C. parapsilosis is reported here for the first time in cider. The analysis of Saccharomyces mtDNA patterns showed great diversity, sequential substitution and the presence of a small number of yeast patterns (up to 8), present in both harvests. Killer (patterns nos. 22′ and 47), sensitive (patterns nos. 12, 15, 33 and 61) and neutral phenotypes were found among the S. cerevisiae isolates. The detection of β-glucosidase activity, with arbutin as the sole carbon source, allowed two S. cerevisiae strains (patterns nos. 3′ and 19′) to be differentiated by means of this enzymatic activity. Yeast strains producing the killer toxin or with β-glucosidase activity are reported for the first time in autochthonous cider yeasts.

Cell population heterogeneity in Mycobacterium tuberculosis H37Rv

The laboratory strain H37Rv represents one of the most commonly used strains in the study of Mycobacterium tuberculosis. Despite the apparent stability of the strain, the absence of a selective pressure for virulence factors could lead to the in vitro accumulation of attenuated mutants. To assess this hypothesis, we performed a systematic analysis of individual clones isolated from subcultured M. tuberculosis H37Rv and from a non-subcultured frozen stock. First, we studied two virulence indicators: neutral red staining and content of phthiocerol dimycocerosates (PDIMs). We found that H37Rv formed a mixed population containing wild-type cells, as well as neutral red and PDIM mutants. Then, we compared the global gene expression of 3 isolated clones (which displayed various phenotypes) and the non-subcultured stock, by microarray analysis. This transcriptional profiling confirmed that a significant heterogeneity existed despite, and in addition to, the neutral red and PDIM phenotypes. These results strongly suggest that great caution must be taken in extrapolating data obtained with M. tuberculosis H37Rv grown in vitro, and it would be prudent to study several independent clones to obtain valid conclusions. For this purpose, the neutral red and PDIM phenotypes might be useful indicators of undesired heterogeneity.

Neutral phenotypes as network keystone species

AbstractThe concept of network keystone species is proposed. A set of phenotypes constitute a network that acts as a functional keystone. When an ecosystem forms a large, complex network that changes temporally, it is generally difficult to tell which will become a keystone species. Based on simulations of abstract ecosystems, phenotypes were classified to show that neutral phenotypes, or slowly reproducing phenotypes, are candidates for keystone species. I show that the removal of neutral phenotypes breaks up an attractor state and produces significant impacts on the stability of an attractor, in spite of small population size. The effect of partial removal of neutral phenotypes, and the combinatorial effects of keystone species, are reported in detail.

Dynamical Systems Approach to Higher-level Heritability.

To explain higher-level heritability, we propose a dynamical systems approach, based on simulations of the high-dimensional replicator equation with mutation dynamics. We assume that all variants are generated from within the groups of variants through mutations. Simulating the equation with a random interaction matrix and possible variants, we report that this system tends to have many attractors, of fixed point, chaotic and quasiperiodic type. In a chaotic attractor, special gene-like variants appear to control the heritability ofthe system, in the sense that removal of the variants would easily enable the system to depart from the attractor. Those variants do not predominate in thepopulation size, but have the lowest net reproduction and mutation rates on average. Because their rate of growth is small, they are named neutral phenotypes. Additionally, combinatorial effects of these neutral variants to the entire system are reported.

Genotypes with phenotypes: Adventures in an RNA toy world

Evolution has created the complexity of the animate world and deciphering the language of evolution is the key towards understanding nature. The dynamics of evolution is simplified by considering it as a superposition of three less sophisticated processes: population dynamics, population support dynamics, and genotype-phenotype mapping. Evolution of molecules in laboratory assays provides a sufficiently simple system for the quantitative analysis of the three phenomena. Coarse-grained notions of structures like RNA secondary structures are used as model phenotypes. They provide an excellent tool for a comprehensive analysis of the entire complex of molecular evolution. The mapping from RNA genotypes into secondary structures is highly redundant. In order to find at least one sequence for every common structures one need only search a (relatively) small part of sequence space. The existence of selectively neutral phenotypes plays an important role for the the success and the efficiency of evolutionary optimization. Molecular evolution found a highly promising technological application in the design of biomolecules with predefined properties.

Occurrence of the killer character in yeasts associated with Spanish wine production

The occurrence of neutral, sensitive or killer phenotypes in 270 oenological yeast strains belonging to 18 species was studied. Strains were isolated from a total of 54 samples representing spontaneous fermentations at 11 wineries of the three Madrid viticultural areas (Arganda, Navalcarnero and San Martı́n de Valdeiglesias). The percentage of strains with the killer phenotype was 42·6% but this percentage varied during the fermentation: 18·8% in must, 50·0% in the middle and 58·8% by late fermentation. The highest frequency of the killer phenotype occurred in the species Saccharomyces cerevisiae (86·9%). Killer activity for this species was shown to result from toxins in the K 2 and K 3 groups.

A new species of double-stranded RNA from yeast.

A NEW species of double-stranded RNA has been detected in certain strains of bakers' yeast, Saccharomyces cerevisiae, during investigations of the chemical nature of the cytoplasmic genetic determinants concerned with the killer character in yeast. There are three phenotypes with respect to this killer phenomenon: killer, sensitive and neutral. Killer cells kill sensitive cells by secreting into the medium a toxic polypeptide1,2 to which they themselves are immune. Neutral cells neither kill nor are killed. The phenomenon is under the control of at least one nuclear gene and two types of cytoplasmic determinant, (k) and (n), which confer the killer and neutral phenotypes respectively3–5.