The genetic circuits that regulate cellular functions are subject to stochastic fluctuations, or `noise', in the levels of their components. Noise, far from just a nuisance, has begun to be appreciated for its essential role in key cellular activities. Noise functions in both microbial and eukaryotic cells, in multicellular development, and in evolution. It enables coordination of gene expression across large regulons, as well as probabilistic differentiation strategies that function across cell populations. At the longest timescales, noise may facilitate evolutionary transitions. Here we review examples and emerging principles that connect noise, the architecture of the gene circuits in which it is present, and the biological functions it enables. We further indicate some of the important challenges and opportunities going forward.

Developmental patterning relies on morphogen gradients, which generally involve feedback loops to buffer against perturbations caused by fluctuations in gene dosage and expression. Although many gene components involved in such feedback loops have been identified, how they work together to generate a robust pattern remains unclear. Here we study the network of extracellular proteins that patterns the dorsal region of the Drosophila embryo by establishing a graded activation of the bone morphogenic protein (BMP) pathway. We find that the BMP activation gradient itself is robust to changes in gene dosage. Computational search for networks that support robustness shows that transport of the BMP class ligands (Scw and Dpp) into the dorsal midline by the BMP inhibitor Sog is the key event in this patterning process. The mechanism underlying robustness relies on the ability to store an excess of signalling molecules in a restricted spatial domain where Sog is largely absent. It requires extensive diffusion of the BMP-Sog complexes, coupled with restricted diffusion of the free ligands. We show experimentally that Dpp is widely diffusible in the presence of Sog but tightly localized in its absence, thus validating a central prediction of our theoretical study.

restricted source, and the rate of its production may Weizmann Institute of Science vary due to genetic alterations or fluctuations in temper-Rehovot 76100 ature or nutrients. Yet, a reliable pattern is established Israel despite such fluctuations. Temporal averaging could provide one mechanism for buffering fluctuations in gene expression. However, such a mechanism would not apply to cases of persistent changes, such as alter-Summary ation in gene dosage. In the Drosophila wing imaginal disc, for example, it was shown that intermediate in-Morphogen gradients provide long-range positional crease in Dpp expression has little effect on wing and information by extending across a developing field. To thorax patterning (Morimura et al., 1996). While similar ensure reproducible patterning, their profile is invariexperiments were not yet done for Wg and Hh morphoable despite genetic or environmental fluctuations. gens, it is known that wing patterning is precise in het-Common models assume a morphogen profile that erozygous mutants that have only one functional allele decays exponentially. Here, we show that exponential of Hh or Wg. profiles cannot, at the same time, buffer fluctuations An emerging theme is that feedback mechanisms play in morphogen production rate and define long-range a prominent role in shaping morphogen gradients (Freegradients. To comply with both requirements, morphoman, 2000; Perrimon and McMahon, 1999). Regulatory gens should decay rapidly close to their source but mechanisms were identified at all levels of morphogen at a significantly slower rate over most of the field. function, including movement away from the source Numerical search revealed two network designs that support robustness to fluctuations in morphogen pro-(Bellaiche et al., 1998; Burke et al., 1999; Chen and duction rate. In both cases, morphogens enhance their Struhl, 1996), stability (Cadigan et al., 1998; Gerlitz and own degradation, leading to a higher degradation rate Basler, 2002; Giraldez et al., 2002), and the sensitivity close to their source. This is achieved through reciproof the receiving cells to morphogen signaling (Campbell cal interactions between the morphogen and its recepand Tomlinson, 1999; Jazwinska et al., 1999). Recently, tor. The two robust networks are consistent with propthe roles of receptors in shaping morphogen gradients erties of the Wg and Hh morphogens in the Drosophila received much interest. Theoretical analysis demonwing disc and provide novel insights into their function. strated that high binding affinities may hinder ligand diffusion, but biologically relevant gradients can still be formed by diffusion, when receptor-mediated ligand Introduction degradation is taken into account (Kerszberg and Wolpert, 1998; Lander et al., 2002). Feedback regulation Morphogens are signaling molecules that induce disof receptor expression was identified for all three mortinct cell fates at different concentrations. During develphogens patterning the Drosophila wing disc (Cadigan, opment, gradients of morphoge...

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Development normally occurs similarly in all individuals within an isogenic population, but mutations often affect the fate of individual organisms differently1-4. This phenomenon, known as partial penetrance, has been observed in diverse developmental systems. However, it remains unclear how the underlying genetic network specifies the set of possible alternative fates and how the relative frequencies of these fates evolve5-8. Here, we identify a stochastic cell fate determination process that operates in Bacillus subtilis sporulation mutants and show how it allows genetic control of the penetrance of multiple fates. Mutations in an inter-compartmental signaling process generate a set of discrete alternative fates not observed in wild-type cells, including rare formation of two viable “twin” spores, rather than one within a single cell. By genetically modulating chromosome replication and septation, we could systematically tune the penetrance of each mutant fate. Furthermore, signaling and replication perturbations synergize to dramatically increase the penetrance of twin sporulation. These results suggest a potential pathway for developmental evolution between monosporulation and twin sporulation through states of intermediate twin penetrance. Furthermore, time-lapse microscopy of twin sporulation in wild-type Clostridium oceanicum showed a strong resemblance to twin sporulation in these B. subtilis mutants9,10. Together the results suggest that noise can facilitate developmental evolution by enabling the initial expression of discrete morphological traits at low penetrance, and allowing their stabilization by gradual adjustment of genetic parameters.

Amphiphilic tobramycin analogues with potent antibacterial activity against tobramycin‐resistant bacteria were synthesized. Most analogues were found to be less prone to deactivation by aminoglycoside‐modifying enzymes than tobramycin. These compounds target the bacterial membrane rather than the ribosome (see picture). The lipophilic residue of these analogues is key to their antibacterial potency and selectivity towards bacterial membranes.

Evolutionary expansion of signaling pathway families often underlies the evolution of regulatory complexity. Expansion requires the acquisition of a novel homologous pathway and the diversification of pathway specificity. Acquisition can occur either vertically, by duplication, or through horizontal transfer, while divergence of specificity is thought to occur through a promiscuous protein intermediate. The way by which these mechanisms shape the evolution of rapidly diverging signaling families is unclear. Here, we examine this question using the highly diversified Rap-Phr cell–cell signaling system, which has undergone massive expansion in the genus Bacillus. To this end, genomic sequence analysis of >300 Bacilli genomes was combined with experimental analysis of the interaction of Rap receptors with Phr autoinducers and downstream targets. Rap-Phr expansion is shown to have occurred independently in multiple Bacillus lineages, with >80 different putative rap-phr alleles evolving in the Bacillius subtilis group alone. The specificity of many rap-phr alleles and the rapid gain and loss of Rap targets are experimentally demonstrated. Strikingly, both horizontal and vertical processes were shown to participate in this expansion, each with a distinct role. Horizontal gene transfer governs the acquisition of already diverged rap-phr alleles, while intralocus duplication and divergence of the phr gene create the promiscuous intermediate required for the divergence of Rap-Phr specificity. Our results suggest a novel role for transient gene duplication and divergence during evolutionary shifts in specificity.

The opportunistic pathogen Pseudomonas aeruginosa employs a hierarchical quorum-sensing network to regulate virulence factor production that cooperatively benefit the population at a cost to the individual. It has been argued that the evolution of a cooperative mutant in a quorum sensing-suppressed population would be hampered through its exploitation by neighboring non-mutant cells. It remains unclear whether mechanisms which overcome this exploitation exist. Here we investigate the regain of quorum-sensing cooperation by evolving a mutant of the lasR master quorum-sensing regulator. The mutant regained partial cooperative growth through null mutations in mexT, which codes for an activator of the MexEF-OprN multidrug-resistant pump. We find that these mutations enhance cooperative growth in both the lasR mutant and wild-type backgrounds through the activation of the RhlIR system. We show that the regain of cooperation in mexT mutants is mediated by the reduction in MexEF-OprN activity, whereas an additional source of private benefit is mostly mexEF-oprN-independent. Finally, we show that addition of antibiotics for which resistance is mediated by MexEF-OprN prevents the selection of increased cooperation at sub-MIC concentrations. MexT, therefore, not only links private and public goods, but also exposes conflicts between selection for antibiotic resistance and enhanced cooperation.