Optimality and evolution of transcriptionally regulated gene expression

<p>Abstract</p> <p>Background</p> <p>How transcriptionally regulated gene expression evolves under natural selection is an open question. The cost and benefit of gene expression are the driving factors. While the former can be determined by gratuitous induction, the latter is difficult to measure directly.</p> <p>Results</p> <p>We addressed this problem by decoupling the regulatory and metabolic function of the <it>Escherichia coli lac </it>system, using an inducer that cannot be metabolized and a carbon source that does not induce. Growth rate measurements directly identified the induced expression level that maximizes the metabolism benefits minus the protein production costs, without relying on models. Using these results, we established a controlled mismatch between sensing and metabolism, resulting in sub-optimal transcriptional regulation with the potential to improve by evolution. Next, we tested the evolutionary response by serial transfer. Constant environments showed cells evolving to the predicted expression optimum. Phenotypes with decreased expression emerged several hundred generations later than phenotypes with increased expression, indicating a higher genetic accessibility of the latter. Environments alternating between low and high expression demands resulted in overall rather than differential changes in expression, which is explained by the concave shape of the cross-environmental tradeoff curve that limits the selective advantage of altering the regulatory response.</p> <p>Conclusions</p> <p>This work indicates that the decoupling of regulatory and metabolic functions allows one to directly measure the costs and benefits that underlie the natural selection of gene regulation. Regulated gene expression is shown to evolve within several hundreds of generations to optima that are predicted by these costs and benefits. The results provide a step towards a quantitative understanding of the adaptive origins of regulatory systems.</p

A Unifying Theory of Biological Function

A new theory that naturalizes biological function is explained and compared with earlier etiological and causal role theories. Etiological theories explain functions from how they are caused over their evolutionary history. Causal role theories analyze how functional mechanisms serve the current capacities of their containing system. The new proposal unifies the key notions of both kinds of theories, but goes beyond them by explaining how functions in an organism can exist as factors with autonomous causal efficacy. The goal-directedness and normativity of functions exist in this strict sense as well. The theory depends on an internal physiological or neural process that mimics an organism’s fitness, and modulates the organism’s variability accordingly. The structure of the internal process can be subdivided into subprocesses that monitor specific functions in an organism. The theory matches well with each intuition on a previously published list of intuited ideas about biological functions, including intuitions that have posed difficulties for other theories

Identification and Inference in a Simultaneous Equation Under Alternative Information Sets and Sampling Schemes

In simple static linear simultaneous equation models the empirical distributions ofIV and OLS are examined under alternative sampling schemes and compared with their first-order asymptotic approximations. It is demonstrated why in this context the limiting distribution of a consistent estimator is not a¤ected by conditioning on exogenous regressors, whereas that of an inconsistent estimator is. The asymptotic variance and the simulated actual variance of the inconsistent OLS estimator are shown to diminish by extending the set of exogenous variables kept fixed in sampling, whereas such an extension disrupts the distribution of consistent IV estimation and deteriorates the accuracy of its standard asymptotic approximation, not only when instruments are weak. Against this background the consequences for the identification of the parameters of interest are examined for a setting in which (in practice often incredible) assumptions regarding the zero correlation between instruments and disturbances are replaced by (generally more credible) interval assumptions on the correlation between endogenous regressors and disturbances. This leads to a feasible procedure for constructing purely OLS-based robust confidence intervals, which yield conservative coverage probabilities in finite samples, and often outperform IV-based intervals regarding their length

From Goya to Afghanistan. An essay on the ratio and ethics of medical war pictures

For centuries pictures of the dead and wounded have been part and parcel of war communications. Often the intentions were clear, ranging from medical instructions to anti-war protests. The public's response could coincide with or diverge from the publisher's intention. Following the invention of photography in the nineteenth century, and the subsequent claim of realism, the veracity of medical war images became more complex. Analysing and understanding such photographs have become an ethical obligation with democratic implications. We performed a multidisciplinary analysis of War Surgery (2008), a book containing harsh, full-colour photographs of mutilated soldiers from the Iraq and Afghanistan wars. Our analysis shows that, within the medical context, this book is a major step forward in medical war communication and documentation. In the military context the book can be conceived as an attempt to put matters right given the enormous sacrifice some individuals have suffered. For the public, the relationship between the 'reality' and 'truth' of such photographs is ambiguous, because only looking at the photographs without reading the medical context is limiting. If the observer is not familiar with medical practice, it is difficult for him to fully assess, signify and acknowledge the value and relevance of this book. We therefore assert the importance of the role of professionals and those in the humanities in particular in educating the public and initiating debate. © 2010 Taylor & Francis