Impact of Epistasis and Pleiotropy on Evolutionary Adaptation

Evolutionary adaptation is often likened to climbing a hill or peak. While this process is simple for fitness landscapes where mutations are independent, the interaction between mutations (epistasis) as well as mutations at loci that affect more than one trait (pleiotropy) are crucial in complex and realistic fitness landscapes. We investigate the impact of epistasis and pleiotropy on adaptive evolution by studying the evolution of a population of asexual haploid organisms (haplotypes) in a model of N interacting loci, where each locus interacts with K other loci. We use a quantitative measure of the magnitude of epistatic interactions between substitutions, and find that it is an increasing function of K. When haplotypes adapt at high mutation rates, more epistatic pairs of substitutions are observed on the line of descent than expected. The highest fitness is attained in landscapes with an intermediate amount of ruggedness that balance the higher fitness potential of interacting genes with their concomitant decreased evolvability. Our findings imply that the synergism between loci that interact epistatically is crucial for evolving genetic modules with high fitness, while too much ruggedness stalls the adaptive process.Comment: 20 pages, 8 figures, plus 10 supporting figure

Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children

BACKGROUND: Targeted temperature management is recommended for comatose adults and children after out-of-hospital cardiac arrest; however, data on temperature management after in-hospital cardiac arrest are limited. METHODS: In a trial conducted at 37 children’s hospitals, we compared two temperature interventions in children who had had in-hospital cardiac arrest. Within 6 hours after the return of circulation, comatose children older than 48 hours and younger than 18 years of age were randomly assigned to therapeutic hypothermia (target temperature, 33.0°C) or therapeutic normothermia (target temperature, 36.8°C). The primary efficacy outcome, survival at 12 months after cardiac arrest with a score of 70 or higher on the Vineland Adaptive Behavior Scales, second edition (VABS-II, on which scores range from 20 to 160, with higher scores indicating better function), was evaluated among patients who had had a VABS-II score of at least 70 before the cardiac arrest. RESULTS: The trial was terminated because of futility after 329 patients had undergone randomization. Among the 257 patients who had a VABS-II score of at least 70 before cardiac arrest and who could be evaluated, the rate of the primary efficacy outcome did not differ significantly between the hypothermia group and the normothermia group (36% [48 of 133 patients] and 39% [48 of 124 patients], respectively; relative risk, 0.92; 95% confidence interval [CI], 0.67 to 1.27; P = 0.63). Among 317 patients who could be evaluated for change in neurobehavioral function, the change in VABS-II score from baseline to 12 months did not differ significantly between the groups (P = 0.70). Among 327 patients who could be evaluated for 1-year survival, the rate of 1-year survival did not differ significantly between the hypothermia group and the normothermia group (49% [81 of 166 patients] and 46% [74 of 161 patients], respectively; relative risk, 1.07; 95% CI, 0.85 to 1.34; P = 0.56). The incidences of blood-product use, infection, and serious adverse events, as well as 28-day mortality, did not differ significantly between groups. CONCLUSIONS: Among comatose children who survived in-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a favorable functional outcome at 1 year. (Funded by the National Heart, Lung, and Blood Institute; THAPCA-IH ClinicalTrials.gov number, NCT00880087.

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present — ‘D’, either elevated blood glucose levels or a family history of diabetes mellitus; ‘K’, the presence of high urinary or blood ketoacids; and ‘A’, a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children

Rugged NK landscapes contain the highest peaks

NK models provide a family of tunably rugged fitness landscapes used in a wide range of evolutionary computation studies. It is well known that the average height of local optima regresses to the mean of the landscape with increasing ruggedness, K. This fact has been confirmed with both theoretical studies of landscape structure and empirical studies of evolutionary search. However, we show mathematically that the global optimum behaves quite differently: the expected value of the global optimum is highest in the maximally rugged case. Furthermore, we demonstrate that this expected value increases with K, despite the fact that the average fitness of the local optima decreases. We find the asymptotic value of the global optimum as N approaches infinity for both the smooth and maximally rugged cases. We interpret these results in the context of evolutionary search, and describe the relationship between the global optimum, local optima and found optima as search effort is geometrically increased

A comparison of neutral landscapes - NK, NKp and NKq

Recent research in molecular evolution has raised awareness of the importance of selective neutrality. Several different models of neutrality have been proposed based on Kauffman’s well-known NK landscape model. Two of these models, NKp and NKq, are investigated and found to display significantly different structural properties. The fitness distributions of these neutral landscapes reveal that their levels of correlation with non-neutral landscapes are significantly different, as are the distributions of neutral mutations. In this paper we describe a series of simulations of a hill climbing search algorithm on NK, NKp and NKq landscapes with varying levels of epistatic interaction. These simulations demonstrate differences in the way that epistatic interaction affects the 'searchability' of neutral landscapes. We conclude that the method used to implement neutrality has an impact on both the structure of the resulting landscapes and on the performance of evolutionary search algorithms on these landscapes. These model-dependent effects must be taken into consideration when modelling biological phenomena

Maximally rugged NK landscapes contain the highest peaks

NK models provide a family of tunably rugged fitness landscapes used in a wide range of evolutionary computation studies. It is well known that the average height of local optima regresses to the mean of the landscape with increasing epistasis, K. This fact has been confirmed using both theoretical studies of landscape structure and empirical studies of evolutionary search. We show that the global optimum behaves quite differently: the expected value of the global maximum is highest in the maximally rugged case. Furthermore, we demonstrate that this expected value increases with K, despite the fact that the average fitness of the local optima decreases. That is, the highest peaks are found in the most rugged landscapes, scattered amongst masses of low-lying peaks. We find the asymptotic value of the global optimum as N approaches infinity for both the smooth and maximally rugged cases. In evolutionary search, the optima that are found reflect the local optima that exist in the landscape, the size of these optima - which corresponds to the size of their basins of attraction, and the effort expended in the search process. Increasing the level of epistasis in an NK landscape stochastically introduces higher peaks, but renders them exponentially more difficult to find. Copyright 2005 ACM

Longitudinal, mixed method study to look at the experiences and knowledge of non melanoma skin cancer from diagnosis to one year

Background Skin cancer is the most common type of cancer in humans and the incidence is increasing worldwide. Our objective was to understanding the needs, experiences and knowledge of individuals with Non Melanoma Skin Cancer (NMSC) from diagnosis up until one year. Methods Patients with NMSC completed questionnaires at diagnosis, treatment, 8 weeks post treatment and 12 months post diagnosis. Body image, psychological morbidity and Quality of Life (QOL) were assessed at each time point, with the exception of QOL that was not assessed at diagnosis. Knowledge of NMSC was assessed at baseline and 8 weeks. A sub-sample of participants was also interviewed to allow a more in-depth exploration of patients’ experiences. Results 76 participants completed the initial questionnaire, of which 15 were interviewed. Patients were anxious about a diagnosis of skin cancer, however they were no more depressed or anxious than the general population. QOL significantly improved from diagnosis to 8 weeks and from diagnosis to one year. Knowledge of NMSC was poor and did not improve after treatment. Hairdressers were highlighted as playing an important role in raising awareness and encouraging individuals to seek medical help. Most participants were aware of the need to check their skin for suspicious lesions but were not sure what to look for. At one year participants had forgotten their experience and were not overly concerned about skin cancer. Conclusion There is a need to raise awareness of the signs and symptoms of NMSC. Information on skin cancer needs to be tailored to the individual both at the start of treatment and during the follow up months, ensuring that participants’ needs and expectations are met. Targeting education at individuals in the community who regularly come into contact with skin should help in early identification of NMSC. This is important since skin cancer caught early is easily treatable and delay in presentation leads to larger and more complex lesions which impacts in terms of increased morbidity and increased health care costs