Genomics of Parallel Experimental Evolution in Drosophila.

What are the genomic foundations of adaptation in sexual populations? We address this question using fitness-character and whole-genome sequence data from 30 Drosophila laboratory populations. These 30 populations are part of a nearly 40-year laboratory radiation featuring 3 selection regimes, each shared by 10 populations for up to 837 generations, with moderately large effective population sizes. Each of 3 sets of the 10 populations that shared a selection regime consists of 5 populations that have long been maintained under that selection regime, paired with 5 populations that had only recently been subjected to that selection regime. We find a high degree of evolutionary parallelism in fitness phenotypes when most-recent selection regimes are shared, as in previous studies from our laboratory. We also find genomic parallelism with respect to the frequencies of single-nucleotide polymorphisms, transposable elements, insertions, and structural variants, which was expected. Entirely unexpected was a high degree of parallelism for linkage disequilibrium. The evolutionary genetic changes among these sexual populations are rapid and genomically extensive. This pattern may be due to segregating functional genetic variation that is abundantly maintained genome-wide by selection, variation that responds immediately to changes of selection regime.

Tracking changes in chromosomal arrangements and their genetic content during adaptation.

There is considerable evidence for an adaptive role of inversions, but how their genetic content evolves and affects the subsequent evolution of chromosomal polymorphism remains controversial. Here, we track how life-history traits, chromosomal arrangements and 22 microsatellites, within and outside inversions, change in three replicated populations of Drosophila subobscura for 30 generations of laboratory evolution since founding from the wild. The dynamics of fitness-related traits indicated adaptation to the new environment concomitant with directional evolution of chromosomal polymorphism. Evidence of selective changes in frequency of inversions was obtained for seven of 23 chromosomal arrangements, corroborating a role for inversions in adaptation. The evolution of linkage disequilibrium between some microsatellites and chromosomes suggested that adaptive changes in arrangements involved changes in their genetic content. Several microsatellite alleles increased in frequency more than expected by drift in targeted inversions in all replicate populations. In particular, there were signs of selection in the O3+4 arrangement favouring a combination of alleles in two loci linked to the inversion and changing along with it, although the lack of linkage disequilibrium between these loci precludes epistatic selection. Seven other alleles increased in frequency within inversions more than expected by drift, but were not in linkage disequilibrium with them. Possibly these alleles were hitchhiking along with alleles under selection that were not specific to those inversions. Overall, the selection detected on the genetic content of inversions, despite limited coverage of the genome, suggests that genetic changes within inversions play an important role in adaptation.

Natural gamma radioactivity in the villages of Kanyakumari District, Tamil Nadu, India.

In situ radiometric survey carried out in 81 revenue villages of Kanyakumari District, Tamil Nadu, India, using a portable radiation dosemeter/detector, revealed the existence of radiation hotspots along the coastal belt. A close observation of the coastal villages specifically revealed high background radioactivity in 14 coastal villages. A very high intrinsic anomalous radioactivity of 41.03 µSv h(-1) was observed, in a famous tourist spot in the coastal belt of Kanyakumari District. This is the highest level of radiation registered in South India, which is extremely higher than the permissible world average and is suggestive of causing severe clinical problems on continuous and prolonged exposure.

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.

What determines quality of life in inclusion body myositis?

BACKGROUND: Quality of life (QoL) assessment allows healthcare professionals to appreciate the patient perspective of their disease. This can help us make a better choice from among the various ways we currently measure the severity of a muscle disease such as inclusion body myositis (IBM). However, we cannot assume that QoL in IBM is just related to disease severity as psychosocial factors may play an important role in determining QoL. METHODS: Sixty subjects with IBM had assessments of disease severity and concurrent assessment of mood and QoL using the Short-Form 36 (SF-36). RESULTS: There were significant reductions in Physical functioning, Role physical, General health and Social functioning domains of the SF-36. Functional disability was more indicative of the broader effects of IBM on SF-36 than was the muscle strength sum score. Mood was relatively independent of disease severity and had a different profile of effects on SF-36 domains. Up to 14% of the effect of functional disability on some aspects of QoL was mediated through mood. CONCLUSIONS: The functional disability caused by IBM reduces QoL, but psychosocial factors such as mood affect QoL directly and by influencing the degree to which disease severity reduces QoL. Further study should follow the effects of IBM on QoL over time and look at the influence of other psychosocial factors. Such studies may point to psychosocial interventions that may help improve QoL in IBM even if the disease itself cannot be treated.

Italian validation of INQoL, a quality of life questionnaire for adults with muscle diseases.

BACKGROUND AND PURPOSE: A quality of life (QoL) questionnaire for neuromuscular diseases was recently constructed and validated in the United Kingdom in a sample of adult patients with a variety of muscle disorders. Preliminary results suggested it could be a more relevant and practical measure of QoL in muscle diseases than generic health measures of QoL. The purpose of our work was: (i) To validate INQoL in Italy on a larger sample of adult patients with muscle diseases (ii) to compare INQoL to SF-36. METHODS: We have translated into Italian and applied language adaptations to the original UK INQoL version. We studied 1092 patients with different muscle disorders and performed (i) test-retest reliability (n = 80); (ii) psychometric (n = 345), known-group (n = 1092), external criterion (n = 70), and concurrent validity with SF-36 (n = 183). RESULTS: We have translated and formally validated the Italian version of INQoL confirming and extending results obtained in the United Kingdom. In addition to good results in terms of reliability, known-group and criterion validity, a comparison with the SF-36 scales showed a stronger association between INQoL total index and SF-36 physical (r = -0.72) than mental (r = -0.38) summary health indexes. When considering comparable domains of INQoL and SF-36 with respect to an objective measure of muscle strength assessment (MMRC), regression analysis showed a stronger correlation using INQoL rather than SF-36 scores. CONCLUSIONS: INQoL is recommended to assess QoL in muscle diseases because of its ability to capture physical limitations that are specifically relevant to the muscle condition.

Treatment for periodic paralysis.

BACKGROUND: Primary periodic paralyses are rare inherited muscle diseases characterised by episodes of flaccid weakness affecting one or more limbs, lasting several hours to several days, caused by mutations in skeletal muscle channel genes. OBJECTIVES: The objective of this review was to systematically review treatment of periodic paralyses. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register, MEDLINE (from January 1966 to July 2007), and EMBASE (from January 1980 to July 2007) and any other available international medical library sources from the University of Milan for randomised trials. SELECTION CRITERIA: We included randomised (including cross-over studies) and quasi-randomised trials in participants with primary periodic paralyses, in which any form of treatment, including physical therapy and alternative therapies, was compared to placebo or another treatment. DATA COLLECTION AND ANALYSIS: Our primary outcome measure was the change in attack severity or frequency by eight weeks from the start of treatment. Our secondary outcome measures were: change in muscle strength and mass; change in Quality of Life, using Short Form 36 (SF36) or similar; preference of treatment strategy; adverse effects at eight weeks. MAIN RESULTS: Three studies met our inclusion criteria. In one study dichlorphenamide (DCP) vs placebo was tested in two groups of participants: 42 with hypokalemic periodic paralysis (HypoPP) and 31 with hyperkalemic periodic paralysis (HyperPP), based on clinical criteria. Thirty-four of 42 participants with hypokalemic periodic paralysis completed both treatment phases. For the 34 participants having attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.02) and severity-weighted attack rate (P = 0.01) on DCP relative to placebo were statistically significant. Fifteen preferred DCP, three placebo and six their baseline medication. Twenty-four of 31 participants with hyperkalemic periodic paralysis completed both treatment phases: for the 16 participants who had attack rate data for both treatment phases, the mean improvement in attack rate (P = 0.006) and in severity-weighted attack rate (P = 0.02) on DCP relative to placebo were significant. Fifteen preferred DCP, one placebo and five their baseline medication. Acetazolamide proved to improve muscle strength in eight participants with HypoPP in one other study and pinacidil, a potassium channel opener, also improved muscle strength in 2/4 participants with HypoPP in a third study. AUTHORS' CONCLUSIONS: The largest included study that met our inclusion criteria suggested that DCP was effective in the prevention of episodic weakness in both hypokalemic and hyperkalemic periodic paralyses. The other two studies provide some evidence that either acetazolamide or pinacidil may improve muscle strength. However we still lack sufficient evidence to provide full guidelines for the treatment of people with periodic paralysis.

Abundant, diverse, and consequential P elements segregate in promoters of small heat-shock genes in Drosophila populations.

The present study extends evidence that Drosophila heat-shock genes are distinctively evolvable because of insertion of transposable elements by examining the genotypic diversity and phenotypic consequences of naturally occurring P element insertions in the proximal promoter regions of two small heat-shock genes. Detailed scrutiny of two populations revealed 16 distinctive P transposable elements collectively segregating in proximal promoters of two small heat-shock genes, Hsp26 and Hsp27. These elements vary in size, orientation and insertion site. Frequencies of P element-containing alleles varied from 5% to 100% in these populations. Two Hsp26 elements chosen for detailed study, R(s)P(26) and D(2)P(m), reduced or abolished Hsp26 expression respectively. The R(s)P(26) element increased or did not affect inducible tolerance of high temperature, increased fecundity, but decreased developmental rate. On the other hand, the D(2)P(m) element decreased thermotolerance and fecundity. In lines subjected to experimental evolution, the allelic frequency of the R(s)P(26)P element varied considerably, and was at lower frequencies in lines selected for increased longevity and for accelerated development than in controls. Transposable element insertions into small Hsp genes in Drosophila populations can have dramatic fitness consequences, and therefore create variation on which selection can act.

Construction and validation of a quality of life questionnaire for neuromuscular disease (INQoL).

BACKGROUND: Because there is no muscle disease specific measure of quality of life (QoL), we wanted to develop and validate an individualized muscle disease specific measure of QoL for adults suitable for both clinical and research use. METHODS: A literature review exploring QoL and its measurement resulted in the development of a theoretical model of QoL. This was used alongside qualitative interviews (n = 41) and a postal survey (n = 252) to design a questionnaire. The psychometric properties, validity (n = 95), reliability (n = 40), and responsiveness (n = 25) of the scale were assessed. RESULTS: The Individualized Neuromuscular Quality of Life questionnaire (INQoL) consists of 45 questions within 10 sections. Four of these focus on the impact of key muscle disease symptoms (weakness, locking [i.e., myotonia], pain, and fatigue), five look at the impact (degree and importance of impact) muscle disease has on particular areas of life, and one section asks about the positive and negative effects of treatment. The questionnaire is structured to allow for variations in the individual characteristics that influence quality of life. Psychometric evaluation established construct validity and test-retest reliability. A preliminary assessment of responsiveness was obtained. CONCLUSIONS: The Individualized Neuromuscular Quality of Life is a validated muscle disease specific measure of quality of life developed from the experiences of patients with muscle disease and can be used for individuals or large samples.

Evolutionary domestication in Drosophila subobscura.

The domestication of plants and animals is historically one of the most important topics in evolutionary biology. The evolutionary genetic changes arising from human cultivation are complex because of the effects of such varied processes as continuing natural selection, artificial selection, deliberate inbreeding, genetic drift and hybridization of different lineages. Despite the interest of domestication as an evolutionary process, few studies of multicellular sexual species have approached this topic using well-replicated experiments. Here we present a comprehensive study in which replicated evolutionary trajectories from several Drosophila subobscura populations provide a detailed view of the evolutionary dynamics of domestication in an outbreeding animal species. Our results show a clear evolutionary response in fecundity traits, but no clear pattern for adult starvation resistance and juvenile traits such as development time and viability. These results supply new perspectives on the confounding of adaptation with other evolutionary mechanisms in the process of domestication.

Evolution of late-life fecundity in Drosophila melanogaster.

Late-life fecundity has been shown to plateau at late ages in Drosophila analogously to late-life mortality rates. In this study, we test an evolutionary theory of late life based on the declining force of natural selection that can explain the occurrence of these late-life plateaus in Drosophila. We also examine the viability of eggs laid by late-age females and test a population genetic mechanism that may be involved in the evolution of late-life fecundity: antagonistic pleiotropy. Together these experiments demonstrate that (i) fecundity plateaus at late ages, (ii) plateaus evolve according to the age at which the force of natural selection acting on fecundity reaches zero, (iii) eggs laid by females in late life are viable and (iv) antagonistic pleiotropy is involved in the evolution of late-life fecundity. This study further supports the evolutionary theory of late life based on the age-specific force of natural selection.

The Effects of Evolution are Local: Evidence from Experimental Evolution in Drosophila.

One of the enduring temptations of evolutionary theory is the extrapolation from short-term to long-term, from a few species to all species. Unfortunately, the study of experimental evolution reveals that extrapolation from local to general patterns of evolution is not usually successful. The present article supports this conclusion using evidence from the experimental evolution of life-history in Drosophila. The following factors demonstrably undermine evolutionary correlations between functional characters: inbreeding, genotype-by-environment interaction, novel foci of selection, long-term selection, and alternative genetic backgrounds. The virtual certainty that at least one of these factors will arise during evolution shreds the prospects for global theories of the effects of adaptation. The effects of evolution apparently don't generalize, even though evolution is a global process.

Evaluation of neuromuscular symptoms in UK Gulf War veterans: a controlled study.

OBJECTIVES: To determine whether Gulf War veterans with neuromuscular symptoms that included weakness and fatigue had either 1) objective correlates for muscle weakness or fatigue; or 2) any etiologic explanation for such symptoms; and if so, 3) whether such objective measures or etiologic mechanisms were specific to Gulf War service. METHODS: Forty-nine ill Gulf War veterans with more than four neuromuscular symptoms (Gulf-ill) were compared with 26 Gulf-well veterans, 13 symptomatic Bosnian veterans (Bosnia-ill), and 22 symptomatic troops who were not deployed to the Gulf (Era-ill). Quantitative myometry was used to objectively measure weakness and fatigue. Subjects had an ischemic forearm exercise test, a subanaerobic bicycle exercise test, and a muscle biopsy. RESULTS: Quantitative strength and fatigue measures did not correlate with self-perception of weakness or fatigue for any of our groups. No specific muscle biopsy abnormalities were found. There was no defect of adenylate deaminase or glycogenolysis found. Gulf-ill subjects did find the subanaerobic bicycle exercise more effortful and generated significantly higher plasma lactate concentrations compared with Gulf-well subjects. CONCLUSION: Because complaints of weakness and fatigue in unwell servicemen do not correlate with actual weakness or fatigue, explanations for these symptoms must lie outside of the neuromuscular system. Increased lactate production during subanaerobic bicycle exercise reflects mitochondrial inefficiency, but it is unclear whether this reflects mitochondrial damage sustained during Gulf War service or inactivity secondary to ill health.

Drug treatment for facioscapulohumeral muscular dystrophy.

BACKGROUND: Facioscapulohumeral muscular dystrophy is a progressive muscle disease which has no agreed treatment. Early suggestions that corticosteroids might be helpful were not supported by a subsequent open label study. The beta 2 adrenergic agonist albuterol, also known as salbutamol, is known to have anabolic effects which might be beneficial for facioscapulohumeral muscular dystrophy. Creatine has been used as a muscle performance enhancer by athletes and it might be helpful in muscular dystrophies including facioscapulohumeral muscular dystrophy. OBJECTIVES: The objective of the review was to determine whether there is any drug treatment which alters the progression of facioscapulohumeral muscular dystrophy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group specialised register (searched August 2003), MEDLINE (January 1966 to August 2003) and EMBASE (January 1980 to August 2003) for any references to facioscapulohumeral muscular dystrophy. Abstracts from the major neurological meetings and trial bibliographies were also searched for further references to trials. Experts were contacted for information regarding unpublished trials or trials in progress. SELECTION CRITERIA: We included all randomised or quasi-randomised trials of any drug treatment for facioscapulohumeral muscular dystrophy, in adults with a recognised diagnosis of facioscapulohumeral muscular dystrophy. Trials had to include an assessment of muscle strength at one year. DATA COLLECTION AND ANALYSIS: All identified trials were independently assessed by both reviewers to ensure that they fulfilled the selection criteria and were then rated for their quality. Trial data were extracted and entered by one reviewer and checked by the other. If appropriate data existed a weighted treatment effect was to be calculated across trials using the Cochrane statistical package, Review Manager. The results were to have been expressed as relative risks and 95% confidence intervals and risk differences and 95% confidence intervals for dichotomous outcomes, and weighted mean differences and 95% confidence intervals for continuous outcomes. MAIN RESULTS: Two published high quality randomised controlled trials fulfilled the selection criteria. One compared creatine supplementation with placebo and the other compared high and low-dose albuterol with placebo. A further unpublished randomised controlled trial of albuterol in facioscapulohumeral muscular dystrophy was identified. The creatine trial showed a non-significant difference in favour of creatine. The albuterol trial showed no significant difference in muscle strength at one year but some secondary measures such as lean body mass and handgrip strength did improve. REVIEWERS' CONCLUSIONS: There is no evidence from randomised controlled trials to support any drug treatment for facioscapulohumeral muscular dystrophy but only two randomised controlled trials have been published.

Scapular fixation in muscular dystrophy.

BACKGROUND: Winging of the scapula is caused by weakness of the thoracoscapular muscles, which allows the scapula to lift off the chest wall during shoulder movements. In facioscapulohumeral muscular dystrophy (and occasionally in other muscular dystrophies) there is selective weakness of the thoracoscapular muscles which may spare other shoulder muscles such as the deltoid muscle. This imbalance results in significant winging and loss of shoulder function. Historically, a number of different surgical and non-surgical interventions have been used to achieve scapular stability. This review examines the evidence available for the use of all scapular fixation techniques in muscular dystrophy, especially facioscapulohumeral muscular dystrophy. OBJECTIVES: To examine the evidence for the relative efficacy of scapular fixation techniques in muscular dystrophy (especially fascioscapulohumeral muscular dystrophy) in improving upper limb function. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group trials register (search updated March 2003) for randomised trials and other reports, and made enquiries from authors of trials and other experts in the field. SELECTION CRITERIA: All reports of scapular fixation for muscular dystrophy, including quasi-randomised or randomised controlled trials, comparing any form of scapular fixation (surgical and non-surgical) in people (of all ages and of all severity) with scapular winging due to muscular dystrophy. Our primary outcome measure was objective improvement in shoulder abduction. Our secondary outcome measures were: patient-perceived improvement in performance of activities of daily living, cosmetic results, subjective improvement in pain and proportion of patients with significant postoperative complications. DATA COLLECTION AND ANALYSIS: We collated and summarised studies on the treatment of scapular winging in muscular dystrophy. MAIN RESULTS: No randomised trials were identified. We therefore present a review of the non-randomised literature available. REVIEWER'S CONCLUSIONS: Operative interventions appear to produce significant benefits, though these have to be balanced against postoperative immobilisation, need for physiotherapy and potential complications. We conclude that a randomised trial would be difficult, but a register of cases and the use of a standardised assessment protocol would allow more accurate comparison of the disparate techniques.

Neurophysiologic analysis of neuromuscular symptoms in UK Gulf War veterans: a controlled study.

BACKGROUND: UK veterans who were deployed to the Gulf in 1990 to 1991 reported higher prevalence of neuromuscular symptoms. OBJECTIVE: To investigate whether these Gulf War-related symptoms were associated with objective evidence of neuromuscular dysfunction. METHODS: Forty-nine Gulf War veterans with more than four neuromuscular symptoms (Gulf-ill), 26 Gulf-well veterans, 13 symptomatic Bosnian veterans (Bosnia-ill), and 22 symptomatic veterans who were not deployed to the Gulf (Era-ill) underwent detailed neurophysiologic assessment: nerve conduction studies, quantitative sensory and autonomic testing, and concentric needle and single-fiber electromyography (EMG). RESULTS: Nerve conduction studies detected carpal tunnel syndrome in two Gulf-ill, two Gulf-well, one Bosnia-ill, and three Era-ill veterans. Ulnar neuropathy was detected in one Gulf-ill and two Era-ill veterans. However, results of detailed nerve conduction studies of the Gulf-ill veterans were comparable with results observed in the other three groups. Quantitative sensory and autonomic assessments also failed to show any specific abnormalities in the Gulf-ill group. Similarly, quantitative assessment of concentric needle and single-fiber EMG detected no chronic denervation or myopathic changes or any abnormalities of neuromuscular transmission in the Gulf-ill veterans. CONCLUSION: Gulf War-related neuromuscular symptoms are not associated with specific impairments of peripheral nerves, neuromuscular junctions, or skeletal muscles.

Intravenous immunoglobulin in neurological disease: a specialist review.

Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control trials will be difficult to deliver. Meanwhile, the treatment is costly and pressure to "do something" in often distressing disorders considerable. This review follows a 1 day meeting of the authors in November 2000 and examines current evidence for the use of IVIg in neurological conditions and comments on mechanisms of action, delivery, safety and tolerability, and health economic issues. Evidence of efficacy has been classified into levels for healthcare interventions (tables 1 and 2).

A prospective natural history study of inclusion body myositis: implications for clinical trials.

Eleven patients with untreated inclusion body myositis (IBM) were prospectively studied during a 6-month period that included muscle strength, lean body mass, and muscle mass measurements. There was an overall quantifiable mean decline in percent of predicted normal muscle strength of 4% from baseline in a 6-month period, but one third of patients showed no change or slight improvements in strength. Short-term treatment trials in IBM will require large numbers of patients to detect slowing, arrest, or even slight improvement in muscle strength.