Genes for which homologs can be detected only in a limited group of evolutionarily related species, called "lineage-specific genes," are pervasive: Essentially every lineage has them, and they often ...comprise a sizable fraction of the group's total genes. Lineage-specific genes are often interpreted as "novel" genes, representing genetic novelty born anew within that lineage. Here, we develop a simple method to test an alternative null hypothesis: that lineage-specific genes do have homologs outside of the lineage that, even while evolving at a constant rate in a novelty-free manner, have merely become undetectable by search algorithms used to infer homology. We show that this null hypothesis is sufficient to explain the lack of detected homologs of a large number of lineage-specific genes in fungi and insects. However, we also find that a minority of lineage-specific genes in both clades are not well explained by this novelty-free model. The method provides a simple way of identifying which lineage-specific genes call for special explanations beyond homology detection failure, highlighting them as interesting candidates for further study.
Evolutionary novelty is difficult to define. It typically involves shifts in organismal or biochemical phenotypes that can be seen as qualitative as well as quantitative changes. In laboratory-based ...experimental evolution of novel phenotypes and the human domestication of crops, the majority of the mutations that lead to adaptation are loss-of-function mutations that impair or eliminate the function of genes rather than gain-of-function mutations that increase or qualitatively alter the function of proteins. Here, I speculate that easier access to loss-of-function mutations has led them to play a major role in the adaptive radiations that occur when populations have access to many unoccupied ecological niches. I discuss five possible objections to this claim: that genes can only survive if they confer benefits to the organisms that bear them, antagonistic pleiotropy, the importance of pre-existing genetic variation in populations, the danger that adaptation by breaking genes will, over long times, cause organisms to run out of genes, and the recessive nature of most loss-of-function mutations.
Andrew Murray proposes that mutations that impair gene function play a major role in the evolution of novel traits.
New Findings
What is the topic of this review?
This report describes changes in cardiac and skeletal muscle energy metabolism that occur with exposure to high altitude and considers possible ...underlying mechanisms.
What advances does it highlight?
In the human heart, sustained hypoxia at high altitude or shorter‐term normobaric hypoxia result in a loss of cardiac energetic reserve. In the hypoxic rat heart, fatty acid oxidation and respiratory capacity fall. In skeletal muscle, prolonged exposure to extreme high altitude results in the loss of mitochondrial density, but even at more moderate high altitude the respiratory capacity may be suppressed. Evidence from cells, genetically modified mice and high‐altitude‐adapted Tibetans suggests a possible mechanistic role for the hypoxia‐inducible factor pathway.
At high altitude the barometric pressure falls, challenging oxygen delivery to the tissues. Thus, whilst hypoxia is not the only physiological stress encountered at high altitude, low arterial PO2 is a sustained feature, even after allowing adequate time for acclimatization. Cardiac and skeletal muscle energy metabolism is altered in subjects at, or returning from, high altitude. In the heart, energetic reserve falls, as indicated by lower phosphocreatine‐to‐ATP ratios. The underlying mechanism is unknown, but in the hypoxic rat heart fatty acid oxidation and respiratory capacity are decreased, whilst pyruvate oxidation is also lower after sustained hypoxic exposure. In skeletal muscle, there is not a consensus. With prolonged exposure to extreme high altitude (>5500 m) a loss of muscle mitochondrial density is seen, but this was not observed in a simulated ascent of Everest in hypobaric chambers. At more moderate high altitude, decreased respiratory capacity may occur without changes in mitochondrial volume density, and fat oxidation may be downregulated, although this is not seen in all studies. The underlying mechanisms, including the possible role of hypoxia‐signalling pathways, remain to be resolved, particularly in light of confounding factors in the high‐altitude environment. In high‐altitude‐adapted Tibetan natives, however, there is evidence of natural selection centred around the hypoxia‐inducible factor pathway, and metabolic features in this population (e.g. low cardiac phosphocreatine‐to‐ATP ratios, increased cardiac glucose uptake and lower muscle mitochondrial densities) share similarities with those in acclimatized lowlanders, supporting a possible role for the hypoxia‐inducible factor pathway in the metabolic response of cardiac and skeletal muscle energy metabolism to high altitude.
New Findings
What is the topic of this review?
This report describes changes in cardiac and skeletal muscle energy metabolism that occur with exposure to high altitude and considers possible underlying mechanisms.
What advances does it highlight?
In the human heart, sustained hypoxia at high altitude or shorter‐term normobaric hypoxia result in a loss of cardiac energetic reserve. In the hypoxic rat heart, fatty acid oxidation and respiratory capacity fall. In skeletal muscle, prolonged exposure to extreme high altitude results in the loss of mitochondrial density, but even at more moderate high altitude the respiratory capacity may be suppressed. Evidence from cells, genetically modified mice and high‐altitude‐adapted Tibetans suggests a possible mechanistic role for the hypoxia‐inducible factor pathway.
Signaling through the cyclic adenosine monophosphate-dependent protein kinase protein kinase A (PKA) is an important and widely studied area of signal transduction research. This signaling pathway is ...commonly investigated through the use of the pharmacological PKA inhibitors H89 and KT 5720. Both of these compounds are thought to block PKA actions through competitive inhibition of the adenosine triphosphate site on the PKA catalytic subunit. Recently, a number of studies have identified actions of H89 and KT 5720 that are independent of their effects on PKA. These nonspecific effects are widespread; they include actions on other protein kinases and signaling molecules and also on basic cellular functions, such as transcription. Here, I summarize the nonspecific effects of these two compounds and compare their actions with those of other PKA inhibitors.
We use the budding yeast, Saccharomyces cerevisiae, to investigate one model for the initial emergence of multicellularity: the formation of multicellular aggregates as a result of incomplete cell ...separation. We combine simulations with experiments to show how the use of secreted public goods favors the formation of multicellular aggregates. Yeast cells can cooperate by secreting invertase, an enzyme that digests sucrose into monosaccharides, and many wild isolates are multicellular because cell walls remain attached to each other after the cells divide. We manipulate invertase secretion and cell attachment, and show that multicellular clumps have two advantages over single cells: they grow under conditions where single cells cannot and they compete better against cheaters, cells that do not make invertase. We propose that the prior use of public goods led to selection for the incomplete cell separation that first produced multicellularity.
Neural control of the function of visceral organs is essential for homeostasis and health. Intestinal peristalsis is critical for digestive physiology and host defence, and is often dysregulated in ...gastrointestinal disorders
. Luminal factors, such as diet and microbiota, regulate neurogenic programs of gut motility
, but the underlying molecular mechanisms remain unclear. Here we show that the transcription factor aryl hydrocarbon receptor (AHR) functions as a biosensor in intestinal neural circuits, linking their functional output to the microbial environment of the gut lumen. Using nuclear RNA sequencing of mouse enteric neurons that represent distinct intestinal segments and microbiota states, we demonstrate that the intrinsic neural networks of the colon exhibit unique transcriptional profiles that are controlled by the combined effects of host genetic programs and microbial colonization. Microbiota-induced expression of AHR in neurons of the distal gastrointestinal tract enables these neurons to respond to the luminal environment and to induce expression of neuron-specific effector mechanisms. Neuron-specific deletion of Ahr, or constitutive overexpression of its negative feedback regulator CYP1A1, results in reduced peristaltic activity of the colon, similar to that observed in microbiota-depleted mice. Finally, expression of Ahr in the enteric neurons of mice treated with antibiotics partially restores intestinal motility. Together, our experiments identify AHR signalling in enteric neurons as a regulatory node that integrates the luminal environment with the physiological output of intestinal neural circuits to maintain gut homeostasis and health.
Cells must couple cell-cycle progress to their growth rate to restrict the spread of cell sizes present throughout a population. Linear, rather than exponential, accumulation of Whi5, was proposed to ...provide this coordination by causing a higher Whi5 concentration in cells born at a smaller size. We tested this model using the inducible GAL1 promoter to make the Whi5 concentration independent of cell size. At an expression level that equalizes the mean cell size with that of wild-type cells, the size distributions of cells with galactose-induced Whi5 expression and wild-type cells are indistinguishable. Fluorescence microscopy confirms that the endogenous and GAL1 promoters produce different relationships between Whi5 concentration and cell volume without diminishing size control in the G1 phase. We also expressed Cln3 from the GAL1 promoter, finding that the spread in cell sizes for an asynchronous population is unaffected by this perturbation. Our findings indicate that size control in budding yeast does not fundamentally originate from the linear accumulation of Whi5, contradicting a previous claim and demonstrating the need for further models of cell-cycle regulation to explain how cell size controls passage through Start.
Background: Rehabilitation nursing lacks a documentation framework representative of nursing's contribution to rehabilitation outcomes. The Rehab ABC nursing documentation framework (Rehab ABC) was ...designed to improve the structure and content of rehabilitation nursing documentation. The framework acts as a mental model and memory aid using a basic mnemonic structure. It contains all the items of the Functional Independence Measure (FIMTM) and additional, comprehensive care responsibilities such as nutrition, pressure care, falls management, cognition and continence care.
Aim: To evaluate introducing the Rehab ABC with the Normalisation Process Theory (NPT) NoMAD survey using two different implementation processes.
Methods: The Rehab ABC was introduced in two independent rehabilitation units using different implementation models of practice development (PD) and quality improvement (QI). The NPT NoMAD survey was used to evaluate four domains of normalisation.
Results: The Rehab ABC had become a normalised process in both units, reflecting how well the framework can be embedded using PD or QI. Providing evidence, the Rehab ABC makes sense and is coherent, creating change using local 'buy-in' through reflexive participation. Audit results reinforced individual and focus group feedback that the Rehab ABC provides users with a logical and understandable framework that supports multidisciplinary team (MDT) communication.
Conclusion: The Rehab ABC provides nurses with a simple sense-making tool to improve documentation and MDT communication. It reflects how rehabilitation nurses integrate functionally focused, comprehensive and goal-oriented rehabilitation in their care. NPT is an easily administered evaluation process that can help guide implementation and gauge the success of the Rehab ABC framework in different clinical contexts.
Synonymous mutations do not alter the encoded protein, but they can influence gene expression. To investigate how, we engineered a synthetic library of 154 genes that varied randomly at synonymous ...sites, but all encoded the same green fluorescent protein (GFP). When expressed in Escherichia coli, GFP protein levels varied 250-fold across the library. GFP messenger RNA (mRNA) levels, mRNA degradation patterns, and bacterial growth rates also varied, but codon bias did not correlate with gene expression. Rather, the stability of mRNA folding near the ribosomal binding site explained more than half the variation in protein levels. In our analysis, mRNA folding and associated rates of translation initiation play a predominant role in shaping expression levels of individual genes, whereas codon bias influences global translation efficiency and cellular fitness.
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