Target-Specific Precision of CRISPR-Mediated Genome Editing.

The CRISPR-Cas9 system has successfully been adapted to edit the genome of various organisms. However, our ability to predict the editing outcome at specific sites is limited. Here, we examined indel profiles at over 1,000 genomic sites in human cells and uncovered general principles guiding CRISPR-mediated DNA editing. We find that precision of DNA editing (i.e., recurrence of a specific indel) varies considerably among sites, with some targets showing one highly preferred indel and others displaying numerous infrequent indels. Editing precision correlates with editing efficiency and a preference for single-nucleotide homologous insertions. Precise targets and editing outcome can be predicted based on simple rules that mainly depend on the fourth nucleotide upstream of the protospacer adjacent motif (PAM). Indel profiles are robust, but they can be influenced by chromatin features. Our findings have important implications for clinical applications of CRISPR technology and reveal general patterns of broken end joining that can provide insights into DNA repair mechanisms.

What can machine learning teach us about habit formation? Evidence from exercise and hygiene.

We apply a machine learning technique to characterize habit formation in two large panel data sets with objective measures of 1) gym attendance (over 12 million observations) and 2) hospital handwashing (over 40 million observations). Our Predicting Context Sensitivity (PCS) approach identifies context variables that best predict behavior for each individual. This approach also creates a time series of overall predictability for each individual. These time series predictability values are used to trace a habit formation curve for each individual, operationalizing the time of habit formation as the asymptotic limit of when behavior becomes highly predictable. Contrary to the popular belief in a "magic number" of days to develop a habit, we find that it typically takes months to form the habit of going to the gym but weeks to develop the habit of handwashing in the hospital. Furthermore, we find that gymgoers who are more predictable are less responsive to an intervention designed to promote more gym attendance, consistent with past experiments showing that habit formation generates insensitivity to reward devaluation.

Unpredictable repeatability in molecular evolution.

The extent of parallel evolution at the genotypic level is quantitatively linked to the distribution of beneficial fitness effects (DBFE) of mutations. The standard view, based on light-tailed distributions (i.e., distributions with finite moments), is that the probability of parallel evolution in duplicate populations is inversely proportional to the number of available mutations and, moreover, that the DBFE is sufficient to determine the probability when the number of available mutations is large. Here, we show that when the DBFE is heavy-tailed, as found in several recent experiments, these expectations are defied. The probability of parallel evolution decays anomalously slowly in the number of mutations or even becomes independent of it, implying higher repeatability of evolution. At the same time, the probability of parallel evolution is non-self-averaging-that is, it does not converge to its mean value, even when a large number of mutations are involved. This behavior arises because the evolutionary process is dominated by only a few mutations of high weight. Consequently, the probability varies widely across systems with the same DBFE. Contrary to the standard view, the DBFE is no longer sufficient to determine the extent of parallel evolution, making it much less predictable. We illustrate these ideas theoretically and through analysis of empirical data on antibiotic-resistance evolution.

On the limits to invasion prediction using coexistence outcomes.

The dynamics of ecological communities in nature are typically characterized by probabilistic processes involving invasion dynamics. Because of technical challenges, however, the majority of theoretical and experimental studies have focused on coexistence dynamics. Therefore, it has become central to understand the extent to which coexistence outcomes can be used to predict analogous invasion outcomes relevant to systems in nature. Here, we study the limits to this predictability under a geometric and probabilistic Lotka-Volterra framework. We show that while individual survival probability in coexistence dynamics can be fairly closely translated into invader colonization probability in invasion dynamics, the translation is less precise between community persistence and community augmentation, and worse between exclusion probability and replacement probability. These results provide a guiding and testable theoretical framework regarding the translatability of outcomes between coexistence and invasion outcomes when communities are represented by Lotka-Volterra dynamics under environmental uncertainty.

Comparison of Pocock and Simon's covariate-adaptive randomization procedures in clinical trials.

When multiple influential covariates need to be balanced during a clinical trial, stratified blocked randomization and covariate-adaptive randomization procedures are frequently used in trials to prevent bias and enhance the validity of data analysis results. The latter approach is increasingly used in practice for a study with multiple covariates and limited sample sizes. Among a group of these approaches, the covariate-adaptive procedures proposed by Pocock and Simon are straightforward to be utilized in practice. We aim to investigate the optimal design parameters for the patient treatment assignment probability of their developed three methods. In addition, we seek to answer the question related to the randomization performance when additional covariates are added to the existing randomization procedure. We conducted extensive simulation studies to address these practically important questions.

Boldness predicts foraging behaviour, habitat use and chick growth in a central place marine predator.

Animal personality can shape individual's fitness. Yet, the mechanistic relationship by which individual's personality traits lead to variations in fitness remains largely underexplored. Here, we used novel object tests to measure boldness of chick-provisioning Cory's shearwaters (Calonectris borealis) from a coastal colony off west Portugal, and deployed GPS loggers to study their at-sea behaviour and distribution. We then tested whether boldness predicts individual differences in adult's trophic ecology and variations in chick growth, to assess potential implications of personality-specific foraging behaviours. Foraging effort was higher for shyer than for bolder individuals, which, during short forays, exhibited larger foraging ranges, and foraged in regions of higher and more variable bathymetry. This suggests that nearby the colony bolder individuals expanded their foraging area to maximize resource acquisition and increase the probability of foraging success. When endeavouring to longer distances, bolder individuals exhibited comparably shorter foraging ranges and targeted low bathymetry regions, likely with enhanced prey availability, while shyer individuals exhibited much larger foraging ranges indicating greater flexibility when foraging in oceanic realms. Despite such differences between bolder and shyer individuals their isotopic niches were similar. Yet, chicks raised by bolder parents grew at a faster rate than those raised by shyer parents. Together, our results suggest that differences in resource acquisition strategies could play a key role through which individual's boldness may influence breeding performance, even when individuals have similar isotopic preferences.

Neurophysiological evidence of motor preparation in inner speech and the effect of content predictability.

Self-generated overt actions are preceded by a slow negativity as measured by electroencephalogram, which has been associated with motor preparation. Recent studies have shown that this neural activity is modulated by the predictability of action outcomes. It is unclear whether inner speech is also preceded by a motor-related negativity and influenced by the same factor. In three experiments, we compared the contingent negative variation elicited in a cue paradigm in an active vs. passive condition. In Experiment 1, participants produced an inner phoneme, at which an audible phoneme whose identity was unpredictable was concurrently presented. We found that while passive listening elicited a late contingent negative variation, inner speech production generated a more negative late contingent negative variation. In Experiment 2, the same pattern of results was found when participants were instead asked to overtly vocalize the phoneme. In Experiment 3, the identity of the audible phoneme was made predictable by establishing probabilistic expectations. We observed a smaller late contingent negative variation in the inner speech condition when the identity of the audible phoneme was predictable, but not in the passive condition. These findings suggest that inner speech is associated with motor preparatory activity that may also represent the predicted action-effects of covert actions.

Mediating effects of predictability between caregiving demands and caregiving consequences for persons living with dementia: A longitudinal study.

OBJECTIVES: The purpose of this study was to examine the role of predictability in the relationship between caregiving demands and caregiving consequences. DESIGN: This 2-year longitudinal survey study collected from self-report questionnaires. A convenience sample of family caregivers of older persons living with dementia were recruited from a neurology clinic. RESULTS: A total of 200 family caregivers were recruited to participate. Analysis indicated predictability was a partial mediator between caregiving demand and caregiver consequences of role strain, depressive symptoms and both physical and mental components of health-related quality of life at the 2-year follow. Predictability accounted for 25 %, 28.8 %, 15.3 % and 46.5 % of the relationship between caregiving demand and caregiving consequences of role strain, depressive symptoms, physical- and mental-health related quality of life, respectively. CONCLUSIONS: The contributions of caregiving demand to outcomes of caregiver consequences were in part due family caregivers perceived predictability for caregiving.

Does aligner refinement have the same efficiency in deep bite correction?: A retrospective study.

BACKGROUND: Refinements are very common in clear aligner treatments. The aim of this study is to assess whether the predictability of deep overbite correction is similar over several refinements using clear aligners (Invisalign, Align Technology, San Jose, Calif) and examine the accuracy of vertical movement and inclination change of individual teeth. METHODS: This retrospective study included 20 deep bite patients (7M and 13F; 32.63 ± 11.88 years old; an initial overbite of 5.09 ± 0.98 mm), consecutively treated from September 2016 and March 2023, who completed at least two sets of aligners, including refinements. The initial, predicted, and achieved models were exported from ClinCheck or OrthoCAD (Cadent Inc, Carlstadt, NJ) and superimposed via best-fit surface-based registration using SlicerCMF (version 4.9.0; cmf.slicer.org). We also examined 15 out of 20 patients who completed treatments. The overbite correction and changes in vertical movement and inclination for individual teeth were measured. Descriptive statistics and a paired t-test or Wilcoxon signed-rank test were performed. P < 0.05 was considered statistically significant. RESULTS: The mean accuracy of overbite correction was 37.63% after 1st set, followed by 11.19%, 6.32%, and 13.80% (2nd-4th sets), respectively. There were statistically significant differences between the predicted and achieved vertical movements and inclination changes for all teeth for the 1st and 2nd sets. For the completed cases, the mean overbite correction was 38.54% compared to the initially planned overbite correction, which is similar to one of the 1st set. Still, the vertical movements and inclination changes of all teeth present statistically significant differences between the initially planned and finally achieved movements except for maxillary lateral incisor torque. CONCLUSIONS: The most overbite correction occurs during the 1st set of aligners, and refinement treatment does not significantly improve the deep bite correction.

Effects of clear aligners on the vertical position of the molar teeth and the vertical and sagittal relationships of the face: a preliminary retrospective before-after clinical trial.

INTRODUCTION: Despite the popularity of clear aligners, their predictability has not been assessed adequately. Moreover, no study has investigated their effects on numerous dentomaxillary variables. Therefore, this study was conducted for the first time, assessing several new or controversial items. The aim of the study was to evaluate the effects of clear aligners on the vertical position of the molar teeth and the vertical and sagittal relationships of the face. METHODS: This preliminary retrospective before-after non-randomized clinical trial was performed on 168 observations of 84 patients (33.60±9.28 years, 54 females) treated with 0.75mm Invisalign appliances. Pretreatment and posttreatment values were measured for: mandibular plane angle, occlusal plane angle, Y-Axis, ANB, facial angle, lower anterior facial height, overbite, and the distances of the molars from the palate and mandibular plane were measured. The alterations in parameters caused by treatment (delta values) were calculated for each measurement. Effects of treatment and some parameters on delta values were analyzed statistically (α=0.05). RESULTS: Mean±SD of ΔMP-FH, ΔOP-FH, ΔY-Axis, ΔLAFH, ΔNPog-FH, ΔANB, ΔOverbite, ΔSNB, Δ6-PP, Δ7-PP, Δ6-MP, and Δ7-MP were respectively 0.11±1.61, 0.80±1.56, 0.15±1.18, 0.07±0.91, -0.22±1.25, 0.03±0.62, 0.04±1.15, -0.06±1.14, -0.36±0.94, -0.32±1.14, 0.19±0.96, 0.18±1.10. Only the alterations in OP-FH, 6-PP, and 7-PP were significant (P≤0.011). Age, sex, treatment duration, or pretreatment mandibular plane angle were not correlated with any delta values. However, the pretreatment occlusal plane angle was negatively correlated with ΔOP-FH and ΔY-Axis. Crowding was correlated negatively with ΔOP-FH and ΔY-Axis and positively with ΔNPog-FH. Overjet was negatively correlated with ΔANB and ΔOverbite (P≤0.035). CONCLUSIONS: Invisalign intruded first/second maxillary molars and increased the occlusal plane angle. Age, sex, and treatment duration were not correlated with post-treatment anatomic alterations.

Predictability of expansion movements performed by clear aligners in mixed dentition in both arches: a retrospective study on digital casts.

BACKGROUND: to evaluate the predictability of expansion achieved in patients in early mixed dentition treated with Clear Aligners (CA), analyzing the efficiency of the expansion at the end of the first set of aligners and at the end of the therapy in the upper and lower arch. METHODS: 36 patients (20 F, 16 M; mean age 8.3 ± 1.5 years) were selected retrospectively from the Department of Orthodontics of the Hospital of Rome "Tor Vergata". All subjects were treated with CA with no other auxiliaries than attachments. For each patient a standardized sequential expansion protocol was planned for both arches. Digital dental casts were created at three observation periods from an intraoral scanner: prior to treatment (T0), at the end of the first set of aligners (T1), at the end of treatment (T2). The 3D models in planned position determined by the first Clincheck (CC) were obtained for comparison with T1 and T2. Six linear transversal measurements were used to evaluate the dimensional changes and the predictability of expansion movements, comparing T1-CC and T2-CC. RESULTS: a statistically significant increase within the pre-treatment and the final outcomes for all the variables examined was found. In the upper arch, the greatest level of predictability was detected at the level of the first (46.44%) and second deciduous molar width (44.95%) at T1. The analysis of T2-CC changes showed a significant increase in the percentage of predictability of expansion at the level of the first permanent molars, at mesial (54.86%) and distal (58.92%) width. In the lower arch, a higher percentage of predictability than the upper arch was reported at T1-CC and T2-CC, with the greatest values at the level of second (T1-CC: 48.70%; T2-CC: 75.32%) and first deciduous molar width (T1-CC: 45.71%; T2-CC: 72.75%). CONCLUSIONS: CA can induce significant transversal increments. The predictability of expansion is variable, but it did not exceed the 50% during the first set of aligners. It was necessary to apply refinement set to achieve a good predictability for expansion of about 70%. The expansion in the lower arch was observed to be more predictable than in the upper arch.

Quantifying animals' perception of environmental predictability using anticipatory behavior.

Animals under human care often experience predictable daily husbandry events, which can promote the development of anticipatory behavior. Previous research suggests even short delays in the arrival of a predictable, desired outcome can lead to negative welfare outcomes for animals. As such, providing reliable information to animals regarding the onset of important events may be a simple but useful method to support positive welfare. Here we evaluated the quantitative characteristics of anticipatory behavior of a California sea lion at the San Francisco Zoo in three situations (1) when the animal had accurate information about the occurrence of the event (temporally predictable training sessions), (2) when the information was semi-reliable (unscheduled training session), and (3) when a reliable signal was offered before unscheduled sessions. Results showed that providing a reliable cue resulted in a stronger temporal correlation of anticipation before the beginning of the unscheduled session, similar to the temporally predictable training session. However, providing a reliable cue did not reduce the intensity of the anticipatory behavior. We propose to take into account two aspects of the quantitative characteristics of anticipatory behavior: correlation with time until a desired event (correlation) and intensity, where the correlation indicates the ability of an individual animal to predict the occurrence of an event, and the intensity indicates the degree of sensitivity of the animal to reward. We discuss the implications for animal welfare and husbandry.

The predictability of arch expansion with the Invisalign First system in children with mixed dentition: a retrospective study.

This study aimed to quantify the predictability of arch expansion in children with early mixed dentition treated with the Invisalign First® system and evaluate the clinical factors for the predictability of arch expansion. Pretreatment, predicted and posttreatment digital models from Invisalign's ClinCheck® software were obtained for 90 children with mean (standard deviation) age of 8.42 (0.93) who planned arch expansion. Arch width measurements were collected using Invisalign's arch width table. The predictability of expansion was calculated by comparing the amount of expansion achieved with the predicted expansion. Linear regression analysis was used to evaluate clinical factors associated with predictability of expansion. The predictability of the expansion of the maxillary teeth was as follows: 71.1% primary canines (n = 55), 67.5% first primary molars (n = 46), 65.2% second primary molars (n = 79), and 53.4% first permanent molars (n = 90); the predictability of the expansion of the mandibular teeth was 81.1% primary canines (n = 31), 81.2% first primary molars (n = 51), 77.8% second primary molars (n = 80), and 69.4% first permanent molars (n = 90). The predictability of arch expansion was significantly higher in the mandibular arch compared to the maxillary arch and significantly lower in the permanent first molar than in the other primary teeth. Predictability decreased significantly as the amount of predicted expansion per aligner increased in the upper and lower permanent first molars, primary second molars, and upper primary canines. Predictability significantly increased when buccal or palatal attachments were placed on the bilateral side compared to cases without attachment at the upper permanent first and primary second molars. The predictability of arch expansion using the Invisalign First® system varies according to arch and tooth type. The amount of predicted expansion per aligner and the number of attachments to the maxillary teeth are potential clinical factors that can affect the predictability of expansion.

Refractive outcomes of small lenticule extraction (SMILE) Pro® with a 2 MHz femtosecond laser.

PURPOSE: To evaluate the initial visual outcomes of Small Incision Lenticule Extraction (SMILE) Pro® using a 2 MHz femtosecond laser (VisuMax 800, Carl Zeiss Meditec) and to assess the efficacy, safety, predictability, accuracy, and complication rate. METHODS: This retrospective analysis included eyes which underwent the SMILE Pro® procedure using VisuMax 800 femtosecond laser to correct myopia. All surgeries were performed by one surgeon (DB). Follow-up was conducted 3 months postoperatively to evaluate visual outcomes after neuroadaptation, corrected visual acuity (CDVA) and intra- and postoperative complications. RESULTS: One hundred and fifty-two eyes of 82 patients (mean age 31 ± 6 years) results at 3 months are presented. The mean spherical equivalent (SE) was - 4.44 ± 1.86 D preoperatively while -0.24 ± 0.32 D postoperatively. 99% of eyes achieved SE within ± 1.0 D of attempted correction and 91% were within ± 0.5 D. Efficacy index was 0.93 while the safety index was 1. No complications occurred intra- or postoperatively. No eyes lost more than 1 line of their preoperative CDVA. All highly myopic eyes (- 6.25 to - 10.00 D; n = 18) achieved 20/20 at 3 months postoperatively and were within 0.5 D from the attempted SE and no eyes lost more than 1 line of CDVA. CONCLUSION: The SMILE Pro® is a safe, efficient, and predictable procedure for the treatment of myopia and myopic astigmatism, with comparable results of conventional SMILE surgery. High myopic eyes achieve better results than low and moderate myopia. No complications were recorded in our patients.

Evolutionary History Mediates Population Response to Rapid Environmental Change through Within-Generational and Transgenerational Plasticity.

AbstractRapid environmental change is affecting many organisms; some are coping well, but many species are in decline. A key mechanism for facilitating success following environmental change is phenotypic plasticity. Organisms use cues to respond phenotypically to environmental conditions; many incorporate recent information (within-generation plasticity) and information from previous generations (transgenerational plasticity). We extend an existing evolutionary model where organisms utilize within-generational plasticity, transgenerational plasticity, and bet hedging to include changes in environmental regime. We show how when rapid evolution of plasticity is not possible, the effect of environmental change (altering the environment mean, variance, or autocorrelation or cue reliability) on population growth rate depends on the population's evolutionary history and past evolutionary responses to historical environmental conditions. We then evaluate the predictions that populations adapted to highly variable environments or with greater within-generational plasticity are more likely to successfully respond to environmental change. We identify when these predictions fail and show that environmental change is most detrimental when previously reliable cues become unreliable. When multiple cues become unreliable, environmental change can cause deleterious effects regardless of the population's evolutionary history. Overall, this work provides a general framework for understanding the role of plasticity in population responses to rapid environmental change.

Planning ahead: Predictable switching recruits task-active and resting-state networks.

Switching is a difficult cognitive process characterised by costs in task performance; specifically, slowed responses and reduced accuracy. It is associated with the recruitment of a large coalition of task-positive regions including those referred to as the multiple demand cortex (MDC). The neural correlates of switching not only include the MDC, but occasionally the default mode network (DMN), a characteristically task-negative network. To unpick the role of the DMN during switching we collected fMRI data from 24 participants playing a switching paradigm that perturbed predictability (i.e., cognitive load) across three switch dimensions-sequential, perceptual, and spatial predictability. We computed the activity maps unique to switch vs. stay trials and all switch dimensions, then evaluated functional connectivity under these switch conditions by computing the pairwise mutual information functional connectivity (miFC) between regional timeseries. Switch trials exhibited an expected cost in reaction time while sequential predictability produced a significant benefit to task accuracy. Our results showed that switch trials recruited a broader activity map than stay trials, including regions of the DMN, the MDC, and task-positive networks such as visual, somatomotor, dorsal, salience/ventral attention networks. More sequentially predictable trials recruited increased activity in the somatomotor and salience/ventral attention networks. Notably, changes in sequential and perceptual predictability, but not spatial predictability, had significant effects on miFC. Increases in perceptual predictability related to decreased miFC between control, visual, somatomotor, and DMN regions, whereas increases in sequential predictability increased miFC between regions in the same networks, as well as regions within ventral attention/ salience, dorsal attention, limbic, and temporal parietal networks. These results provide novel clues as to how DMN may contribute to executive task performance. Specifically, the improved task performance, unique activity, and increased miFC associated with increased sequential predictability suggest that the DMN may coordinate more strongly with the MDC to generate a temporal schema of upcoming task events, which may attenuate switching costs.

Quantifying stochastic establishment of mutants in microbial adaptation.

Studies of microbial evolution, especially in applied contexts, have focused on the role of selection in shaping predictable, adaptive responses to the environment. However, chance events - the appearance of novel genetic variants and their establishment, i.e. outgrowth from a single cell to a sizeable population - also play critical initiating roles in adaptation. Stochasticity in establishment has received little attention in microbiology, potentially due to lack of awareness as well as practical challenges in quantification. However, methods for high-replicate culturing, mutant labelling and detection, and statistical inference now make it feasible to experimentally quantify the establishment probability of specific adaptive genotypes. I review methods that have emerged over the past decade, including experimental design and mathematical formulas to estimate establishment probability from data. Quantifying establishment in further biological settings and comparing empirical estimates to theoretical predictions represent exciting future directions. More broadly, recognition that adaptive genotypes may be stochastically lost while rare is significant both for interpreting common lab assays and for designing interventions to promote or inhibit microbial evolution.

Boosting predictabilities of agronomic traits in rice using bivariate genomic selection.

The multivariate genomic selection (GS) models have not been adequately studied and their potential remains unclear. In this study, we developed a highly efficient bivariate (2D) GS method and demonstrated its significant advantages over the univariate (1D) rival methods using a rice dataset, where four traditional traits (i.e. yield, 1000-grain weight, grain number and tiller number) as well as 1000 metabolomic traits were analyzed. The novelty of the method is the incorporation of the HAT methodology in the 2D BLUP GS model such that the computational efficiency has been dramatically increased by avoiding the conventional cross-validation. The results indicated that (1) the 2D BLUP-HAT GS analysis generally produces higher predictabilities for two traits than those achieved by the analysis of individual traits using 1D GS model, and (2) selected metabolites may be utilized as ancillary traits in the new 2D BLUP-HAT GS method to further boost the predictability of traditional traits, especially for agronomically important traits with low 1D predictabilities.

Understanding natural selection and similarity: Convergent, parallel and repeated evolution.

Parallel and convergent evolution offer some of the most compelling evidence for the significance of natural selection in evolution, as the emergence of similar adaptive solutions is unlikely to occur by random chance alone. However, these terms are often employed inconsistently, leading to misinterpretation and confusion, and recently proposed definitions have unintentionally diminished the emphasis on the evolution of similar adaptive solutions. Here, I examine various conceptual frameworks and definitions related to parallel and convergent evolution and propose a consolidated framework that enhances our comprehension of these evolutionary patterns. The primary aim of this framework is to harmonize the concepts of parallel and convergent evolution together with natural selection and the idea of similarity. Both concepts involve the evolution of similar adaptive solutions as a result of environmental challenges. The distinction lies in ancestral phenotypes. Parallel evolution takes place when the ancestral phenotypes (before selection) of the lineages are similar. Convergent evolution happens when the lineages have distinct ancestral phenotypes (before selection). Because an ancestral-based distinction will inevitably lead to cases where uncertainty in the distinction may arise, the framework includes a general term, repeated evolution, which can be used as a term applying to the evolution of similar phenotypes and genotypes as well as similar responses to environmental pressures. Based on the argument that genetic similarity may frequently arise without selection, the framework posits that the similarity of genetic sequences is not of great interest unless linked to the actions of natural selection or to the origins (mutation, standing genetic variation, gene flow) and locations of the similar sequences.

Os casos de evolução paralela e convergente apresentam-se como provas convincentes da relevância da selecção natural no processo evolutivo, já que é improvável que soluções adaptativas semelhantes evoluam apenas por acaso. No entanto, estes dois termos são utilizados frequentemente de forma inconsistente e as definições recentemente propostas diminuíram involuntariamente a ênfase na evolução de soluções adaptativas semelhantes. Nesta contribuição, examino os quadros conceptuais e definições relacionadas com evolução paralela e convergente e proponho um quadro conceptual consolidado que aumenta a compreensão destes padrões evolutivos. O objectivo desta contribuição é harmonizar os conceitos de evolução paralela e convergente juntamente com os conceitos de selecção natural e de similaridade. Ambos os conceitos implicam a evolução de soluções adaptativas semelhantes como resultado de pressões evolutivas. A distinção reside nos fenótipos ancestrais: A evolução paralela ocorre quando os fenótipos ancestrais (antes da selecção) das linhagens eram semelhantes. A evolução convergente acontece quando as linhagens tinham fenótipos ancestrais distintos (antes da selecção). Dado que uma distinção baseada na ancestralidade de caracteres levará, inevitavelmente, a casos em que a incerteza na distinção pode surgir, sugiro a inclusão de um termo geral: evolução repetida, que pode ser aplicado à evolução de fenótipos e genótipos semelhantes, assim como respostas semelhantes a pressões ambientais. Com base na argumentação de que a similaridade genética pode surgir frequentemente sem selecção, eu postulo que a similitude de sequências genéticas não é de grande interesse, a menos que esteja relacionada às ações da selecção natural ou às origens (mutação, variação genética existente, fluxo génico) e localizações das sequências semelhantes.

La evolución paralela y convergente ofrecen algunas de las pruebas más contundentes de la importancia de la selección natural en la evolución, ya que es improbable que la emergencia de soluciones adaptativas similares se produzca únicamente por casualidad. Sin embargo, estos términos se emplean a menudo forma inconsistente, lo que da lugar a interpretaciones erróneas y confusión. Además, las definiciones recientemente propuestas han restado importancia, involuntariamente, a la evolución de soluciones adaptativas similares. En este artículo, examino diversos marcos conceptuales y definiciones relacionadas con la evolución paralela y convergente, y propongo un marco consolidado que mejora nuestra comprensión de estos patrones evolutivos. El objetivo principal de este marco es armonizar los conceptos de evolución paralela y convergente con la selección natural y la idea de similitud. Ambos conceptos implican la evolución de soluciones adaptativas similares como resultado de presiones evolutivas. La distinción radica en los fenotipos ancestrales: la evolución paralela ocurre cuando los fenotipos ancestrales (antes de la selección) de las linajes eran similares. La evolución convergente se produce cuando las lijanes tenían fenotipos ancestrales distintos (antes de la selección). Dado que una distinción basada en la ancestralidad conducirá inevitablemente a casos en los que puede surgir incertidumbre en la distinción, el marco incluye un término general: evolución repetida, que se puede utilizarse como un término laxo aplicable a la evolución de fenotipos y genotipos similares, así como a respuestas similares a presiones ambientales. Basándose en el argumento de que la similitud genética puede surgir frecuentemente sin selección, el marco postula que la similitud de secuencias genéticas no es de gran interés a menos que esté vinculada a las acciones de la selección natural o a los orígenes (mutación, variación genética existente, flujo genético) y ubicaciones de las secuencias similares.

Genetic Landscape of Major Depressive Disorder: Assessment of Potential Diagnostic and Antidepressant Response Markers.

BACKGROUND: The clinical heterogeneity in major depressive disorder (MDD), variable treatment response, and conflicting findings limit the ability of genomics toward the discovery of evidence-based diagnosis and treatment regimen. This study attempts to curate all genetic association findings to evaluate potential variants for clinical translation. METHODS: We systematically reviewed all candidates and genome-wide association studies for both MDD susceptibility and antidepressant response, independently, using MEDLINE, particularly to identify replicated findings. These variants were evaluated for functional consequences using different in silico tools and further estimated their diagnostic predictability by calculating positive predictive values. RESULTS: A total of 217 significantly associated studies comprising 1200 variants across 545 genes and 128 studies including 921 variants across 412 genes were included with MDD susceptibility and antidepressant response, respectively. Although the majority of associations were confirmed by a single study, we identified 31 and 18 replicated variants (in at least 2 studies) for MDD and antidepressant response. Functional annotation of these 31 variants predicted 20% coding variants as deleterious/damaging and 80.6% variants with regulatory effect. Similarly, the response-related 18 variants revealed 25% coding variant as damaging and 88.2% with substantial regulatory potential. Finally, we could calculate the diagnostic predictability of 19 and 5 variants whose positive predictive values ranges from 0.49 to 0.66 for MDD and 0.36 to 0.66 for response. CONCLUSIONS: The replicated variants presented in our data are promising for disease diagnosis and improved response outcomes. Although these quantitative assessment measures are solely directive of available observational evidence, robust homogenous validation studies are required to strengthen these variants for molecular diagnostic application.