Developmental disorders caused by haploinsufficiency of transcriptional regulators: a perspective based on cell fate determination.

Many human birth defects and neurodevelopmental disorders are caused by loss-of-function mutations in a single copy of transcription factor (TF) and chromatin regulator genes. Although this dosage sensitivity has long been known, how and why haploinsufficiency (HI) of transcriptional regulators leads to developmental disorders (DDs) is unclear. Here I propose the hypothesis that such DDs result from defects in cell fate determination that are based on disrupted bistability in the underlying gene regulatory network (GRN). Bistability, a crucial systems biology concept to model binary choices such as cell fate decisions, requires both positive feedback and ultrasensitivity, the latter often achieved through TF cooperativity. The hypothesis explains why dosage sensitivity of transcriptional regulators is an inherent property of fate decisions, and why disruption of either positive feedback or cooperativity in the underlying GRN is sufficient to cause disease. I present empirical and theoretical evidence in support of this hypothesis and discuss several issues for which it increases our understanding of disease, such as incomplete penetrance. The proposed framework provides a mechanistic, systems-level explanation of HI of transcriptional regulators, thus unifying existing theories, and offers new insights into outstanding issues of human disease. This article has an associated Future Leader to Watch interview with the author of the paper.

Evolution and dysfunction of human cognitive and social traits: A transcriptional regulation perspective.

Evolutionary changes in brain and craniofacial development have endowed humans with unique cognitive and social skills, but also predisposed us to debilitating disorders in which these traits are disrupted. What are the developmental genetic underpinnings that connect the adaptive evolution of our cognition and sociality with the persistence of mental disorders with severe negative fitness effects? We argue that loss of function of genes involved in transcriptional regulation represents a crucial link between the evolution and dysfunction of human cognitive and social traits. The argument is based on the haploinsufficiency of many transcriptional regulator genes, which makes them particularly sensitive to loss-of-function mutations. We discuss how human brain and craniofacial traits evolved through partial loss of function (i.e. reduced expression) of these genes, a perspective compatible with the idea of human self-domestication. Moreover, we explain why selection against loss-of-function variants supports the view that mutation-selection-drift, rather than balancing selection, underlies the persistence of psychiatric disorders. Finally, we discuss testable predictions.

Evolution of reproductive parasites with direct fitness benefits.

Maternally inherited symbionts such as Wolbachia have long been seen mainly as reproductive parasites, with deleterious effects on host fitness. It is becoming clear, however, that, frequently, these symbionts also have beneficial effects on host fitness, either along with reproductive parasitism or not. Using the examples of cytoplasmic incompatibility (CI) and male-killing (MK), we here analyze the effect of direct fitness benefits on the evolution of reproductive parasites. By means of a simple theoretical framework, we synthesize and extend earlier modeling approaches for CI and MK, which usually ignore fitness benefits. Moreover, our framework is not restricted to a particular mechanism underlying the fitness benefit (e.g., protection against pathogens). We derive invasion conditions and equilibrium frequencies for the different infection scenarios. Our results demonstrate the importance of a symbiont's "effective fecundity" (i.e., the product of the relative fecundity of an infected female and her transmission efficiency) for a symbiont's invasion success. In particular, we adopt the concept of effective fecundity to scenarios where CI and MK co-occur in one host population. We confirm that direct fitness benefits substantially facilitate the invasion and spread of infections (for example, by lowering or removing the invasion threshold) or even make invasion possible in the first place (for example, if reproductive parasitism is weak or absent). Finally, we discuss the role of direct fitness benefits in long-term evolutionary dynamics of reproductive phenotypes and highlight their potential to resolve genetic conflicts between maternally inherited symbionts and their hosts.

Wolbachia and the insect immune system: what reactive oxygen species can tell us about the mechanisms of Wolbachia-host interactions.

Wolbachia are intracellular bacteria that infect a vast range of arthropod species, making them one of the most prevalent endosymbionts in the world. Wolbachia's stunning evolutionary success is mostly due to their reproductive parasitism but also to mutualistic effects such as increased host fecundity or protection against pathogens. However, the mechanisms underlying Wolbachia phenotypes, both parasitic and mutualistic, are only poorly understood. Moreover, it is unclear how the insect immune system is involved in these phenotypes and why it is not more successful in eliminating the bacteria. Here we argue that reactive oxygen species (ROS) are likely to be key in elucidating these issues. ROS are essential players in the insect immune system, and Wolbachia infection can affect ROS levels in the host. Based on recent findings, we elaborate a hypothesis that considers the different effects of Wolbachia on the oxidative environment in novel vs. native hosts. We propose that newly introduced Wolbachia trigger an immune response and cause oxidative stress, whereas in coevolved symbioses, infection is not associated with oxidative stress, but rather with restored redox homeostasis. Redox homeostasis can be restored in different ways, depending on whether Wolbachia or the host is in charge. This hypothesis offers a mechanistic explanation for several of the observed Wolbachia phenotypes.

Bad guys turned nice? A critical assessment of Wolbachia mutualisms in arthropod hosts.

Wolbachia are the most abundant bacterial endosymbionts among arthropods. Although maternally inherited, they do not conform to the widespread view that vertical transmission inevitably selects for beneficial symbionts. Instead, Wolbachia are notorious for their reproductive parasitism which, although lowering host fitness, ensures their spread. However, even for reproductive parasites it can pay to enhance host fitness. Indeed, there is a recent upsurge of reports on Wolbachia-associated fitness benefits. Therefore, the question arises how such instances of mutualism are related to the phenotypes of reproductive parasitism. Here, we review the evidence of Wolbachia mutualisms in arthropods, including both facultative and obligate relationships, and critically assess their biological relevance. Although many studies report anti-pathogenic effects of Wolbachia, few actually prove these effects to be relevant to field conditions. We further show that Wolbachia frequently have beneficial and detrimental effects at the same time, and that reproductive manipulations and obligate mutualisms may share common mechanisms. These findings undermine the idea of a clear-cut distinction between Wolbachia mutualism and parasitism. In general, both facultative and obligate mutualisms can have a strong, and sometimes unforeseen, impact on the ecology and evolution of Wolbachia and their arthropod hosts. Acknowledging this mutualistic potential might be the key to a better understanding of some unresolved issues in the study of Wolbachia-host interactions.

Epidemiology in evolutionary time: the case of Wolbachia horizontal transmission between arthropod host species.

Wolbachia are bacterial endosymbionts that manipulate the reproduction of their arthropod hosts. Although theory suggests that infections are frequently lost within host species due to the evolution of resistance, Wolbachia infect a huge number of species worldwide. This apparent paradox suggests that horizontal transmission between host species has been a key factor in shaping the global Wolbachia pandemic. Because Wolbachia infections are thus acquired and lost like any other infection, we use a standard epidemiological model to analyse Wolbachia horizontal transmission dynamics over evolutionary time. Conceptually modifying the model, we apply it not to transmission between individuals but between species. Because, on evolutionary timescales, infections spread frequently between closely related species and occasionally over large phylogenetic distances, we represent the set of host species as a small-world network that satisfies both requirements. Our model reproduces the effect of basic epidemiological parameters, which demonstrates the validity of our approach. We find that the ratio between transmission rate and recovery rate is crucial for determining the proportion of infected species (incidence) and that, in a given host network, the incidence may still be increasing over evolutionary time. Our results also point to the importance of occasional transmission over long phylogenetic distances for the observed high incidence levels of Wolbachia. In conclusion, we are able to explain why Wolbachia are so abundant among arthropods, although selection for resistance within hosts often leads to infection loss. Furthermore, our unorthodox approach of using epidemiology in evolutionary time can be applied to all symbionts that use horizontal transmission to infect new hosts.

Still a host of hosts for Wolbachia: analysis of recent data suggests that 40% of terrestrial arthropod species are infected.

Wolbachia are intracellular bacteria that manipulate the reproduction of their arthropod hosts in remarkable ways. They are predominantly transmitted vertically from mother to offspring but also occasionally horizontally between species. In doing so, they infect a huge range of arthropod species worldwide. Recently, a statistical analysis estimated the infection frequency of Wolbachia among arthropod hosts to be 66%. At the same time, the authors of this analysis highlighted some weaknesses of the underlying data and concluded that in order to improve the estimate, a larger number of individuals per species should be assayed and species be chosen more randomly. Here we apply the statistical approach to a more appropriate data set from a recent survey that tested both a broad range of species and a sufficient number of individuals per species. Indeed, we find a substantially different infection frequency: We now estimate the proportion of Wolbachia-infected species to be around 40% which is lower than the previous estimate but still points to a surprisingly high number of arthropods harboring the bacteria. Notwithstanding this difference, we confirm the previous result that, within a given species, typically most or only a few individuals are infected. Moreover, we extend our analysis to include several reproductive parasites other than Wolbachia that were also screened for in the aforementioned empirical survey. For these symbionts we find a large variation in estimated infection frequencies and corroborate the finding that Wolbachia are the most abundant endosymbionts among arthropod species.