Tandem chimerism as a means to increase protein complexity in the human genome.

The "one-gene, one-protein" rule, coined by Beadle and Tatum, has been fundamental to molecular biology. The rule implies that the genetic complexity of an organism depends essentially on its gene number. The discovery, however, that alternative gene splicing and transcription are widespread phenomena dramatically altered our understanding of the genetic complexity of higher eukaryotic organisms; in these, a limited number of genes may potentially encode a much larger number of proteins. Here we investigate yet another phenomenon that may contribute to generate additional protein diversity. Indeed, by relying on both computational and experimental analysis, we estimate that at least 4%-5% of the tandem gene pairs in the human genome can be eventually transcribed into a single RNA sequence encoding a putative chimeric protein. While the functional significance of most of these chimeric transcripts remains to be determined, we provide strong evidence that this phenomenon does not correspond to mere technical artifacts and that it is a common mechanism with the potential of generating hundreds of additional proteins in the human genome.

A comparison of Bayesian and frequentist approaches to incorporating external information for the prediction of prostate cancer risk.

We present the most comprehensive comparison to date of the predictive benefit of genetics in addition to currently used clinical variables, using genotype data for 33 single-nucleotide polymorphisms (SNPs) in 1,547 Caucasian men from the placebo arm of the REduction by DUtasteride of prostate Cancer Events (REDUCE®) trial. Moreover, we conducted a detailed comparison of three techniques for incorporating genetics into clinical risk prediction. The first method was a standard logistic regression model, which included separate terms for the clinical covariates and for each of the genetic markers. This approach ignores a substantial amount of external information concerning effect sizes for these Genome Wide Association Study (GWAS)-replicated SNPs. The second and third methods investigated two possible approaches to incorporating meta-analysed external SNP effect estimates - one via a weighted PCa 'risk' score based solely on the meta analysis estimates, and the other incorporating both the current and prior data via informative priors in a Bayesian logistic regression model. All methods demonstrated a slight improvement in predictive performance upon incorporation of genetics. The two methods that incorporated external information showed the greatest receiver-operating-characteristic AUCs increase from 0.61 to 0.64. The value of our methods comparison is likely to lie in observations of performance similarities, rather than difference, between three approaches of very different resource requirements. The two methods that included external information performed best, but only marginally despite substantial differences in complexity.

Mucoviscidose: illustration de la complexité du dépistage génétique. [The example of cystic fibrosis to highlight the complexity of genetic screening].

Différentes organisations et différents pays aboutissent souvent à des conclusions différentes quant à la pertinence d'introduire un test de dépistage génétique dans la population générale. Cet article décrit la complexité du dépistage basé sur des tests génétiques. Utilisant l'exemple de la mucoviscidose - pour laquelle un groupe de travail national est en train d'évaluer la pertinence d'un dépistage génétique - les auteurs relèvent les situaions où les recommandations de dépistage sont parfois basées sur l'émergence de nouvelles technologies (par exemple, test génétique) et d'opinion publique plutôt que sur la base d'évidences. Ils présentent également les enjeux éthiques et économiques du dépistage génétique de la mucoviscidose. [Abstract] Various institutions and countries often reach different conclusions about the utility of introducing a newborn screening test in the general population. This paper highlights the complexity of population screening including genetic tests. Using the example of cystic fibrosis genetic screening, for which a Swiss Working Group for Cystic Fibrosis is currently evaluating the pertinence, we outline that screening recommendations are often based more on expert opinion and emerging new technologies rather than on evidence. We also present some ethical and economic issues related to cystic fibrosis genetic screening.

Predicting Non Return to Work after Orthopaedic Trauma: The Wallis Occupational Rehabilitation RisK (WORRK) Model.

BACKGROUND: Workers with persistent disabilities after orthopaedic trauma may need occupational rehabilitation. Despite various risk profiles for non-return-to-work (non-RTW), there is no available predictive model. Moreover, injured workers may have various origins (immigrant workers), which may either affect their return to work or their eligibility for research purposes. The aim of this study was to develop and validate a predictive model that estimates the likelihood of non-RTW after occupational rehabilitation using predictors which do not rely on the worker's background. METHODS: Prospective cohort study (3177 participants, native (51%) and immigrant workers (49%)) with two samples: a) Development sample with patients from 2004 to 2007 with Full and Reduced Models, b) External validation of the Reduced Model with patients from 2008 to March 2010. We collected patients' data and biopsychosocial complexity with an observer rated interview (INTERMED). Non-RTW was assessed two years after discharge from the rehabilitation. Discrimination was assessed by the area under the receiver operating curve (AUC) and calibration was evaluated with a calibration plot. The model was reduced with random forests. RESULTS: At 2 years, the non-RTW status was known for 2462 patients (77.5% of the total sample). The prevalence of non-RTW was 50%. The full model (36 items) and the reduced model (19 items) had acceptable discrimination performance (AUC 0.75, 95% CI 0.72 to 0.78 and 0.74, 95% CI 0.71 to 0.76, respectively) and good calibration. For the validation model, the discrimination performance was acceptable (AUC 0.73; 95% CI 0.70 to 0.77) and calibration was also adequate. CONCLUSIONS: Non-RTW may be predicted with a simple model constructed with variables independent of the patient's education and language fluency. This model is useful for all kinds of trauma in order to adjust for case mix and it is applicable to vulnerable populations like immigrant workers.

A survey of transposable element classification systems--a call for a fundamental update to meet the challenge of their diversity and complexity.

The increase of publicly available sequencing data has allowed for rapid progress in our understanding of genome composition. As new information becomes available we should constantly be updating and reanalyzing existing and newly acquired data. In this report we focus on transposable elements (TEs) which make up a significant portion of nearly all sequenced genomes. Our ability to accurately identify and classify these sequences is critical to understanding their impact on host genomes. At the same time, as we demonstrate in this report, problems with existing classification schemes have led to significant misunderstandings of the evolution of both TE sequences and their host genomes. In a pioneering publication Finnegan (1989) proposed classifying all TE sequences into two classes based on transposition mechanisms and structural features: the retrotransposons (class I) and the DNA transposons (class II). We have retraced how ideas regarding TE classification and annotation in both prokaryotic and eukaryotic scientific communities have changed over time. This has led us to observe that: (1) a number of TEs have convergent structural features and/or transposition mechanisms that have led to misleading conclusions regarding their classification, (2) the evolution of TEs is similar to that of viruses by having several unrelated origins, (3) there might be at least 8 classes and 12 orders of TEs including 10 novel orders. In an effort to address these classification issues we propose: (1) the outline of a universal TE classification, (2) a set of methods and classification rules that could be used by all scientific communities involved in the study of TEs, and (3) a 5-year schedule for the establishment of an International Committee for Taxonomy of Transposable Elements (ICTTE).

Controlling complexity: the clinical relevance of mouse complex genetics.

Experimental animal models are essential to obtain basic knowledge of the underlying biological mechanisms in human diseases. Here, we review major contributions to biomedical research and discoveries that were obtained in the mouse model by using forward genetics approaches and that provided key insights into the biology of human diseases and paved the way for the development of novel therapeutic approaches.

Estimation of reference curves for the urinary steroid metabolome in the first year of life in healthy children : Tracing the complexity of human postnatal steroidogenesis.

CONTEXT: Complex steroid disorders such as P450 oxidoreductase deficiency or apparent cortisone reductase deficiency may be recognized by steroid profiling using chromatographic mass spectrometric methods. These methods are highly specific and sensitive, and provide a complete spectrum of steroid metabolites in a single measurement of one sample which makes them superior to immunoassays. The steroid metabolome during the fetal-neonatal transition is characterized by (a) the metabolites of the fetal-placental unit at birth, (b) the fetal adrenal androgens until its involution 3-6 months postnatally, and (c) the steroid metabolites produced by the developing endocrine organs. All these developmental events change the steroid metabolome in an age- and sex-dependent manner during the first year of life. OBJECTIVE: The aim of this study was to provide normative values for the urinary steroid metabolome of healthy newborns at short time intervals in the first year of life. METHODS: We conducted a prospective, longitudinal study to measure 67 urinary steroid metabolites in 21 male and 22 female term healthy newborn infants at 13 time-points from week 1 to week 49 of life. Urine samples were collected from newborn infants before discharge from hospital and from healthy infants at home. Steroid metabolites were measured by gas chromatography-mass spectrometry (GC-MS) and steroid concentrations corrected for urinary creatinine excretion were calculated. RESULTS: 61 steroids showed age and 15 steroids sex specificity. Highest urinary steroid concentrations were found in both sexes for progesterone derivatives, in particular 20α-DH-5α-DH-progesterone, and for highly polar 6α-hydroxylated glucocorticoids. The steroids peaked at week 3 and decreased by ∼80% at week 25 in both sexes. The decline of progestins, androgens and estrogens was more pronounced than of glucocorticoids whereas the excretion of corticosterone and its metabolites and of mineralocorticoids remained constant during the first year of life. CONCLUSION: The urinary steroid profile changes dramatically during the first year of life and correlates with the physiologic developmental changes during the fetal-neonatal transition. Thus detailed normative data during this time period permit the use of steroid profiling as a powerful diagnostic tool.

Complexity of the Paradigms Present in Quality Criteria of Qualitative Research Grids

With qualitative methods being increasingly used in health science fields, numerous grids proposing criteria to evaluate the quality of this type of research have been produced. Expert evaluators deem that there is a lack of consensual tools to evaluate qualitative research. Based on the review of 133 quality criteria grids for qualitative research in health sciences, the authors present the results of a computerized lexicometric analysis, which confirms the variety of intra- and inter-grid constructions, including within the same field. This variety is linked to the authors' paradigmatic references underlying the criteria proposed. These references seem to be built intuitively, reflecting internal representations of qualitative research, thus making the grids and their criteria hard to compare. Consequently, the consensus on the definitions and the number of criteria becomes problematic. The paradigmatic and theoretical references of the grids should be specified so that users could better assess their contributions and limitations.

Predicted decrease in global climate suitability masks regional complexity of invasive fruit fly species response to climate change

Climate change affects the rate of insect invasions as well as the abundance, distribution and impacts of such invasions on a global scale. Among the principal analytical approaches to predicting and understanding future impacts of biological invasions are Species Distribution Models (SDMs), typically in the form of correlative Ecological Niche Models (ENMs). An underlying assumption of ENMs is that species-environment relationships remain preserved during extrapolations in space and time, although this is widely criticised. The semi-mechanistic modelling platform, CLIMEX, employs a top-down approach using species ecophysiological traits and is able to avoid some of the issues of extrapolation, making it highly applicable to investigating biological invasions in the context of climate change. The tephritid fruit flies (Diptera: Tephritidae) comprise some of the most successful invasive species and serious economic pests around the world. Here we project 12 tephritid species CLIMEX models into future climate scenarios to examine overall patterns of climate suitability and forecast potential distributional changes for this group. We further compare the aggregate response of the group against species-specific responses. We then consider additional drivers of biological invasions to examine how invasion potential is influenced by climate, fruit production and trade indices. Considering the group of tephritid species examined here, climate change is predicted to decrease global climate suitability and to shift the cumulative distribution poleward. However, when examining species-level patterns, the predominant directionality of range shifts for 11 of the 12 species is eastward. Most notably, management will need to consider regional changes in fruit fly species invasion potential where high fruit production, trade indices and predicted distributions of these flies overlap.