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Cancers of various organs have been categorized into distinct subtypes after increasingly sophisticated taxonomies. Additionally, within a seemingly homogeneous subclass, individual cancers contain diverse tumour cell populations that vary in important cancer‐specific traits such as clonogenicity and invasive potential. Differences that exist between and within a given tumour type have hampered significantly both the proper selection of patients that might benefit from therapy, as well as the development of new targeted agents. In this review, we discuss the differences associated with organ‐specific cancer subtypes and the factors that contribute to intra‐tumour heterogeneity. It is of utmost importance to understand the biological causes that distinguish tumours as well as distinct tumour cell populations within malignancies, as these will ultimately point the way to more rational anti‐cancer treatments. EMBO reports advance online publication 12 July 2013; doi:10.1038/embor.2013.92 In this review Jan Paul Medema and colleagues discuss the differences associated with organ‐specific cancer subtypes and the factors that contribute to intra‐tumour heterogeneity. Understanding tumour heterogeneity is crucial for the development of more rational anti‐cancer treatments.

The reaction sequences of central metabolism, glycolysis and the pentose phosphate pathway provide essential precursors for nucleic acids, amino acids and lipids. However, their evolutionary origins are not yet understood. Here, we provide evidence that their structure could have been fundamentally shaped by the general chemical environments in earth's earliest oceans. We reconstructed potential scenarios for oceans of the prebiotic Archean based on the composition of early sediments. We report that the resultant reaction milieu catalyses the interconversion of metabolites that in modern organisms constitute glycolysis and the pentose phosphate pathway. The 29 observed reactions include the formation and/or interconversion of glucose, pyruvate, the nucleic acid precursor ribose‐5‐phosphate and the amino acid precursor erythrose‐4‐phosphate, antedating reactions sequences similar to that used by the metabolic pathways. Moreover, the Archean ocean mimetic increased the stability of the phosphorylated intermediates and accelerated the rate of intermediate reactions and pyruvate production. The catalytic capacity of the reconstructed ocean milieu was attributable to its metal content. The reactions were particularly sensitive to ferrous iron Fe(II), which is understood to have had high concentrations in the Archean oceans. These observations reveal that reaction sequences that constitute central carbon metabolism could have been constrained by the iron‐rich oceanic environment of the early Archean. The origin of metabolism could thus date back to the prebiotic world. Synopsis Modern cells possess a sophisticated metabolic network, but its origins remain largely unknown. Reconstructing scenarios of the Archean ocean, we observe chemical reactions reminiscent of modern metabolic sequences, indicating that metabolism could be of prebiotic origin. Metabolites of glycolysis and the pentose phosphate undergo non‐enzymatic interconversion reactions. Metal ions abundantly found in sediments of the prebiotic Archean ocean, predominantly Fe(II), catalyse additional sugar phosphate interconversion reactions. Reactions catalysed by the Archean ocean metals resemble enzyme‐catalysed reactions found in the modern glycolytic and pentose phosphate pathways. The observed reactions are accelerated and gain specificity in conditions simulating the Archean ocean. Graphical Abstract Modern cells possess a sophisticated metabolic network, but its origins remain largely unknown. Reconstructing scenarios of the Archean ocean, we observe chemical reactions reminiscent of modern metabolic sequences, indicating that metabolism could be of prebiotic origin.

Evidence suggests that novel enzyme functions evolved from low‐level promiscuous activities in ancestral enzymes. Yet, the evolutionary dynamics and physiological mechanisms of how such side activities contribute to systems‐level adaptations are not well characterized. Furthermore, it remains untested whether knowledge of an organism's promiscuous reaction set, or underground metabolism, can aid in forecasting the genetic basis of metabolic adaptations. Here, we employ a computational model of underground metabolism and laboratory evolution experiments to examine the role of enzyme promiscuity in the acquisition and optimization of growth on predicted non‐native substrates in Escherichia coli K‐12 MG1655. After as few as approximately 20 generations, evolved populations repeatedly acquired the capacity to grow on five predicted non‐native substrates—D‐lyxose, D‐2‐deoxyribose, D‐arabinose, m‐tartrate, and monomethyl succinate. Altered promiscuous activities were shown to be directly involved in establishing high‐efficiency pathways. Structural mutations shifted enzyme substrate turnover rates toward the new substrate while retaining a preference for the primary substrate. Finally, genes underlying the phenotypic innovations were accurately predicted by genome‐scale model simulations of metabolism with enzyme promiscuity. Synopsis Computational modeling of underground metabolism, laboratory evolution and omics analyses reveal that enzyme promiscuity can play a major role during adaptation to new growth environments and indicate that the genes underlying the phenotypic innovations can be predicted. Enzyme promiscuity can confer a fitness benefit in novel growth environments and open routes for achieving innovative growth states. Mutation events which enable growth on non‐native carbon sources can be structural or regulatory in nature and single mutation events related to a promiscuous activity can be sufficient to support growth while some cases require multiple mutations. Metabolic network analysis and constraint‐based modeling can predict adaptation to non‐native carbon sources through promiscuous enzyme activities. Laboratory evolution can be used to select for enzymes with structural mutations enabling an improved substrate affinity for a non‐native carbon source. Graphical Abstract Computational modeling of underground metabolism, laboratory evolution and omics analyses reveal that enzyme promiscuity can play a major role during adaptation to new growth environments and indicate that the genes underlying the phenotypic innovations can be predicted.

The hypoxic response in humans is mediated by the hypoxia‐inducible transcription factor (HIF), for which prolyl hydroxylases (PHDs) act as oxygen‐sensing components. The evolutionary origins of the HIF system have been previously unclear. We demonstrate a functional HIF system in the simplest animal, Trichoplax adhaerens : HIF targets in T. adhaerens include glycolytic and metabolic enzymes, suggesting a role for HIF in the adaptation of basal multicellular animals to fluctuating oxygen levels. Characterization of the T. adhaerens PHDs and cross‐species complementation assays reveal a conserved oxygen‐sensing mechanism. Cross‐genomic analyses rationalize the relative importance of HIF system components, and imply that the HIF system is likely to be present in all animals, but is unique to this kingdom. Schofield and colleagues demonstrate that a functional HIF system is present in the simplest animal, Trichoplax adhaerens. Their results imply that the HIF system is conserved in all animals, and reveal conservation of biochemical properties in the oxygen‐sensing machinery

MicroRNAs (miRNAs) modulate transcript stability and translation. Functional mature miRNAs are processed from one or both arms of the hairpin precursor. The miR‐100/10 family has undergone three independent evolutionary events that have switched the arm from which the functional miRNA is processed. The dominant miR‐10 sequences in the insects Drosophila melanogaster and Tribolium castaneum are processed from opposite arms. However, the duplex produced by Dicer cleavage has an identical sequence in fly and beetle. Expression of the Tribolium miR‐10 sequence in Drosophila S2 cells recapitulates the native beetle pattern. Thus, arm usage is encoded in the primary miRNA sequence, but outside the mature miRNA duplex. We show that the predicted messenger RNA targets and inferred function of sequences from opposite arms differ significantly. Arm switching is likely to be general, and provides a fundamental mechanism to evolve the function of a miRNA locus and target gene network. In the miR‐100/10 miRNA family, the arm of the hairpin precursor from which the dominant functional miRNA is processed has switched at least three times during evolution. Arm choice is encoded in the sequence of the primary transcript, and has profound effects on the function of orthologous miRNAs.

After two decades of stardom, one would think that β‐catenin has revealed all of its most intimate details. Yet the essence of its duality has remained mysterious—how can a single protein both be the core link between cadherins and the cytoskeleton, and the nuclear messenger for Wnt signalling? On the basis of the available evidence and on molecular and evolutionary considerations, I propose that β‐catenin was a born nuclear transport receptor, which by interacting with adhesion molecules acquired the property to coordinate nuclear functions with cell–cell adhesion. While Wnt signalling diverted this activity, the original pathway might still function in modern eukaryotes. β‐catenin is both a nuclear messenger for Wnt signalling and part of cell adhesive junctions. Based on structural and functional similarities with importins and exportins, Fagotto hypothesizes that β‐catenin's ancient role was a nuclear transport receptor that could coordinate nuclear functions with cell adhesion. This property might have been exploited by the Wnt pathway.

Reporter gene assays have demonstrated both transcription‐associated mutagenesis (TAM) and transcription‐coupled repair, but the net impact of transcription on mutation rate remains unclear, especially at the genomic scale. Using comparative genomics of related species as well as mutation accumulation lines, we show in yeast that the rate of point mutation in a gene increases with the expression level of the gene. Transcription induces mutagenesis on both DNA strands, indicating simultaneous actions of several TAM mechanisms. A significant positive correlation is also detected between the human germline mutation rate and expression level. These results indicate that transcription is overall mutagenic. Genomic analysis shows that the mutation rate in a gene increases with the expression level of the gene both in yeast as well as in the human germline.

Stress response genes and their regulators form networks that underlie drug resistance. These networks often have an inherent tradeoff: their expression is costly in the absence of stress, but beneficial in stress. They can quickly emerge in the genomes of infectious microbes and cancer cells, protecting them from treatment. Yet, the evolution of stress resistance networks is not well understood. Here, we use a two‐component synthetic gene circuit integrated into the budding yeast genome to model experimentally the adaptation of a stress response module and its host genome in three different scenarios. In agreement with computational predictions, we find that: (i) intra‐module mutations target and eliminate the module if it confers only cost without any benefit to the cell; (ii) intra‐ and extra‐module mutations jointly activate the module if it is potentially beneficial and confers no cost; and (iii) a few specific mutations repeatedly fine‐tune the module's noisy response if it has excessive costs and/or insufficient benefits. Overall, these findings reveal how the timing and mechanisms of stress response network evolution depend on the environment. Synopsis The evolution of a synthetic gene circuit that trades off costly gene expression for drug resistance is analyzed computationally. The predictions are validated experimentally by adjusting gene expression in the absence or presence of environmental stress. A synthetic gene circuit is integrated into the yeast genome to model the evolution of drug resistance networks with inherent tradeoff. Computational models are constructed to predict the speed and mechanisms of adaptation for various levels of gene expression and stress. The cell population adapts by mutations eliminating the module quickly when the network gratuitously responds in the absence of stress or by mutations that fine‐tune the module's suboptimal response and establish slowly in the presence of stress. If the module initially fails to respond to stress, the population adapts by mutations that activate gene expression within the module. Graphical Abstract The evolution of a synthetic gene circuit that trades off costly gene expression for drug resistance is analyzed computationally. The predictions are validated experimentally by adjusting gene expression in the absence or presence of environmental stress.

Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such biases are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most pertinent evidence is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in Escherichia coli that produce a gene expression stripe—a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution. Synopsis Analyses in synthetic circuits show that mutations result in distinct novel phenotypes in two circuits that showed the same phenotype before mutation. This constrained phenotypic variation is caused by differences in the circuits’ regulatory mechanisms. Two synthetic circuits expressed in E. coli that produce the same phenotype, but through different regulatory mechanisms, are used to study the molecular mechanisms underlying constrained phenotypic variation during evolution. The two networks create different spectra of novel phenotypes after mutation. A combination of experimental measurements, mathematical modeling and DNA sequencing shows that the regulatory mechanisms restrict the phenotypic variation that becomes accessible upon mutation. Graphical Abstract Analyses in synthetic circuits show that mutations result in distinct novel phenotypes in two circuits that showed the same phenotype before mutation. This constrained phenotypic variation is caused by differences in the circuits’ regulatory mechanisms.

Prions consist mainly, if not entirely, of PrP Sc , an aggregated conformer of the host protein PrP C . Prions come in different strains, all based on the same PrP C sequence, but differing in their conformations. The efficiency of prion transmission between species is usually low, but increases after serial transmission in the new host, suggesting a process involving mutation and selection. Even within the same species, the transfer of prions between cell types entails a selection of favoured ‘substrains’, and propagation of prions in the presence of an inhibitory drug can result in the appearance of drug‐resistant prion populations. We propose that prion populations are comprised of a variety of conformers, constituting ‘quasi‐species’, from which the one replicating most efficiently in a particular environment is selected. Prion strains have the same sequence but different conformations. Their transmission dynamics suggests that they are subject to mutation—defined as a heritable change in conformation—and selection. Prion populations are proposed to constitute “quasi‐species”, from which the one conformer replicating most efficiently in a particular environment is selected.