Aneuploidy, an abnormal number of chromosomes, is a widespread phenomenon found in unicellulars such as yeast, as well as in plants and in mammalians, especially in cancer. Aneuploidy is a genomescale aberration that imposes a severe burden on the cell, yet under stressful conditions specific aneuploidies confer a selective advantage. This dual nature of aneuploidy raises the question of whether it can serve as a stable and sustainable evolutionary adaptation. To clarify this, we conducted a set of laboratory evolution experiments in yeast and followed the long-term dynamics of aneuploidy under diverse conditions. Here we show that chromosomal duplications are first acquired as a crude solution to stress, yet only as transient solutions that are eliminated and replaced by more efficient solutions obtained at the individual gene level. These transient dynamics of aneuploidy were repeatedly observed in our laboratory evolution experiments; chromosomal duplications gained under stress were eliminated not only when the stress was relieved, but even if it persisted. Furthermore, when stress was applied gradually rather than abruptly, alternative solutions appear to have emerged, but not aneuploidy. Our findings indicate that chromosomal duplication is a first evolutionary line of defense, that retains survivability under strong and abrupt selective pressures, yet it merely serves as a "quick fix," whereas more refined and sustainable solutions take over. Thus, in the perspective of genome evolution trajectory, aneuploidy is a useful yet short-lived intermediate that facilitates further adaptation.evolutionary dynamics | environmental stress | heat tolerance | pH tolerance

Natural habitats of some microorganisms may fluctuate erratically, whereas others, which are more predictable, offer the opportunity to prepare in advance for the next environmental change. In analogy to classical Pavlovian conditioning, microorganisms may have evolved to anticipate environmental stimuli by adapting to their temporal order of appearance. Here we present evidence for environmental change anticipation in two model microorganisms, Escherichia coli and Saccharomyces cerevisiae. We show that anticipation is an adaptive trait, because pre-exposure to the stimulus that typically appears early in the ecology improves the organism's fitness when encountered with a second stimulus. Additionally, we observe loss of the conditioned response in E. coli strains that were repeatedly exposed in a laboratory evolution experiment only to the first stimulus. Focusing on the molecular level reveals that the natural temporal order of stimuli is embedded in the wiring of the regulatory network-early stimuli pre-induce genes that would be needed for later ones, yet later stimuli only induce genes needed to cope with them. Our work indicates that environmental anticipation is an adaptive trait that was repeatedly selected for during evolution and thus may be ubiquitous in biology.

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The Ras-Erk (extracellular signal-regulated kinase) pathway encodes information in its dynamics; the duration and frequency of Erk activity can specify distinct cell fates. To enable dynamic encoding, temporal information must be accurately transmitted from the plasma membrane to the nucleus. We used optogenetic profiling to show that both oncogenic B-Raf mutations and B-Raf inhibitors can cause corruption of this transmission, so that short pulses of input Ras activity are distorted into abnormally long Erk outputs. These changes can reshape downstream transcription and cell fates, resulting in improper decisions to proliferate. These findings illustrate how altered dynamic signal transmission properties, and not just constitutively increased signaling, can contribute to cell proliferation and perhaps cancer, and how optogenetic profiling can dissect mechanisms of signaling dysfunction in disease.

The collection of microbes that live in and on the human bodythe human microbiomecan impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cellcell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biologya systems biology approach.

Cells must interpret environmental information that often changes over time. We systematically monitored growth of yeast cells under various frequencies of oscillating osmotic stress. Growth was severely inhibited at a particular resonance frequency, at which cells show hyperactivated transcriptional stress responses. This behavior represents a sensory misperception - the cells incorrectly interpret oscillations as a staircase of ever-increasing osmolarity. The misperception results from the capacity of the osmolarity-sensing kinase network to retrigger with sequential osmotic stresses. Although this feature is critical for coping with natural challenges — like continually increasing osmolarity — it results in a tradeoff of fragility to non-natural oscillatory inputs that match the retriggering time. These findings demonstrate the value of non-natural dynamic perturbations in exposing hidden sensitivities of cellular regulatory networks.

Survival in natural habitats selects for microorganisms that are well-adapted to a wide range of conditions. Recent studies revealed that cells evolved innovative response strategies that extend beyond merely sensing a given stimulus and responding to it on encounter. A diversity of microorganisms, including Escherichia coli, Vibrio cholerae, and several yeast species, were shown to use a predictive regulation strategy that uses the appearance of one stimulus as a cue for the likely arrival of a subsequent one. A better understanding of such a predictive strategy requires elucidating the interplay between key biological and environmental forces. Here, we describe a mathematical framework to address this challenge. We base this framework on experimental systems featuring early preparation to either a stress or an exposure to improvement in the growth medium. Our model calculates the fitness advantage originating under each regulation strategy in a given habitat. We conclude that, although a predictive response strategy might by advantageous under some ecologies, its costs might exceed the benefit in others. The combined theoreticalexperimental treatment presented here helps assess the potential of natural ecologies to support a predictive behavior.adaptation | conditioning | evolution M icroorganisms are constantly faced with environmental stimuli and stresses. Over the years, cellular response to such challenges has been intensively studied in several model organisms (1-5). Prevalent response strategies follow a sense and respond logic: cells continuously monitor their environment and induce a cellular response to cope with a stimulus on encounter with it. Although evolution selects for improved sensing and response mechanisms, adaptation can also extend and result in the emergence of more sophisticated response strategies. For example, under stochastic switching, cells randomly alternate between potential cellular states. In a fluctuating environment that is hard to monitor, such a response strategy might ensure that a portion of the population is always prepared for unpredicted challenge (6-8).Here, we focus on environments that are characterized by a stereotypical temporal order of stimuli. Previous theoretical work has suggested that such ecologies may select for organisms that use information about the natural sequence of events (8). Recent studies have revealed examples of such adaptations in model microorganisms. Tagkopoulos et al. (9) investigated the response of Escherichia coli to temperature elevation that is followed shortly after by a drop in oxygen availability on entry of bacteria to the host digestive tract and observed an associative anticipatory regulation pattern-each signal by itself can invoke response to both stimuli. In another study, we have shown that E. coli has adapted to the sequential order of exposure to different sugars along the mammalian digestive tract. Additionally, we have shown that this conditioned response entails the bacteria with fitness advantages when cells are exposed...

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