Wolbachia versus dengue: Evolutionary forecasts.

A novel form of biological control is being applied to the dengue virus. The agent is the maternally transmitted bacterium Wolbachia, naturally absent from the main dengue vector, the mosquito Aedes aegypti. Three Wolbachia-based control strategies have been proposed. One is suppression of mosquito populations by large-scale releases of males incompatible with native females; this intervention requires ongoing releases. The other interventions transform wild mosquito populations with Wolbachia that spread via the frequency-dependent fitness advantage of Wolbachia-infected females; those interventions potentially require just a single, local release for area-wide disease control. One of these latter strategies uses Wolbachia that shortens mosquito life, indirectly preventing viral maturation/transmission. The other strategy uses Wolbachia that block viral transmission. All interventions can be undermined by viral, bacterial or mosquito evolution; viral virulence in humans may also evolve. We examine existing theory, experiments and comparative evidence to motivate predictions about evolutionary outcomes. (i) The life-shortening strategy seems the most likely to be thwarted by evolution. (ii) Mosquito suppression has a reasonable chance of working locally, at least in the short term, but long-term success over large areas is challenging. (iii) Dengue blocking faces strong selection for viral resistance but may well persist indefinitely at some level. Virulence evolution is not mathematically predictable, but comparative data provide no precedent for Wolbachia increasing dengue virulence. On balance, our analysis suggests that the considerable possible benefits of these technologies outweigh the known negatives, but the actual risk is largely unknown

Facilitating Wolbachia introductions into mosquito populations through insecticide-resistance selection.

Wolbachia infections are being introduced into mosquito vectors of human diseases following the discovery that they can block transmission of disease agents. This requires mosquitoes infected with the disease-blocking Wolbachia to successfully invade populations lacking the infection. While this process is facilitated by features of Wolbachia, particularly their ability to cause cytoplasmic incompatibility, blocking Wolbachia may produce deleterious effects, such as reduced host viability or fecundity, that inhibit successful local introductions and subsequent spatial spread. Here, we outline an approach to facilitate the introduction and spread of Wolbachia infections by coupling Wolbachia introduction to resistance to specific classes of insecticides. The approach takes advantage of very high maternal transmission fidelity of Wolbachia infections in mosquitoes, complete incompatibility between infected males and uninfected females, the widespread occurrence of insecticide resistance, and the widespread use of chemical control in disease-endemic countries. This approach is easily integrated into many existing control strategies, provides population suppression during release and might be used to introduce Wolbachia infections even with high and seasonally dependent deleterious effects, such as the wMelPop infection introduced into Aedes aegypti for dengue control. However, possible benefits will need to be weighed against concerns associated with the introduction of resistance alleles

Commentary: Fisher's infinitesimal model: A story for the ages.

Mendel (1866) suggested that if many heritable "factors" contribute to a trait, near-continuous variation could result. Fisher (1918) clarified the connection between Mendelian inheritance and continuous trait variation by assuming many loci, each with small effect, and by informally invoking the central limit theorem. Barton et al. (2017) rigorously analyze the approach to a multivariate Gaussian distribution of the genetic effects for descendants of parents who may be related. This commentary distinguishes three nested approximations, referred to as "infinitesimal genetics," "Gaussian descendants" and "Gaussian population," each plausibly called "the infinitesimal model." The first and most basic is Fisher's "infinitesimal" approximation of the underlying genetics - namely, many loci, each making a small contribution to the total variance. As Barton et al. (2017) show, in the limit as the number of loci increases (with enough additivity), the distribution of genotypic values for descendants approaches a multivariate Gaussian, whose variance-covariance structure depends only on the relatedness, not the phenotypes, of the parents (or whether their population experiences selection or other processes such as mutation and migration). Barton et al. (2017) call this rigorously defensible "Gaussian descendants" approximation "the infinitesimal model." However, it is widely assumed that Fisher's genetic assumptions yield another Gaussian approximation, in which the distribution of breeding values in a population follows a Gaussian - even if the population is subject to non-Gaussian selection. This third "Gaussian population" approximation, is also described as the "infinitesimal model." Unlike the "Gaussian descendants" approximation, this third approximation cannot be rigorously justified, except in a weak-selection limit, even for a purely additive model. Nevertheless, it underlies the two most widely used descriptions of selection-induced changes in trait means and genetic variances, the "breeder's equation" and the "Bulmer effect." Future generations may understand why the "infinitesimal model" provides such useful approximations in the face of epistasis, linkage, linkage disequilibrium and strong selection

Deploying dengue-suppressing Wolbachia : Robust models predict slow but effective spatial spread in Aedes aegypti.

A novel strategy for controlling the spread of arboviral diseases such as dengue, Zika and chikungunya is to transform mosquito populations with virus-suppressing Wolbachia. In general, Wolbachia transinfected into mosquitoes induce fitness costs through lower viability or fecundity. These maternally inherited bacteria also produce a frequency-dependent advantage for infected females by inducing cytoplasmic incompatibility (CI), which kills the embryos produced by uninfected females mated to infected males. These competing effects, a frequency-dependent advantage and frequency-independent costs, produce bistable Wolbachia frequency dynamics. Above a threshold frequency, denoted pˆ, CI drives fitness-decreasing Wolbachia transinfections through local populations; but below pˆ, infection frequencies tend to decline to zero. If pˆ is not too high, CI also drives spatial spread once infections become established over sufficiently large areas. We illustrate how simple models provide testable predictions concerning the spatial and temporal dynamics of Wolbachia introductions, focusing on rate of spatial spread, the shape of spreading waves, and the conditions for initiating spread from local introductions. First, we consider the robustness of diffusion-based predictions to incorporating two important features of wMel-Aedes aegypti biology that may be inconsistent with the diffusion approximations, namely fast local dynamics induced by complete CI (i.e., all embryos produced from incompatible crosses die) and long-tailed, non-Gaussian dispersal. With complete CI, our numerical analyses show that long-tailed dispersal changes wave-width predictions only slightly; but it can significantly reduce wave speed relative to the diffusion prediction; it also allows smaller local introductions to initiate spatial spread. Second, we use approximations for pˆ and dispersal distances to predict the outcome of 2013 releases of wMel-infected Aedes aegypti in Cairns, Australia, Third, we describe new data from Ae. aegypti populations near Cairns, Australia that demonstrate long-distance dispersal and provide an approximate lower bound on pˆ for wMel in northeastern Australia. Finally, we apply our analyses to produce operational guidelines for efficient transformation of vector populations over large areas. We demonstrate that even very slow spatial spread, on the order of 10-20 m/month (as predicted), can produce area-wide population transformation within a few years following initial releases covering about 20-30% of the target area

Spatial waves of advance with bistable dynamics: Cytoplasmic and genetic analogues of Allee effects

Unlike unconditionally advantageous “Fisherian” variants that tend to spread throughout a species range once introduced anywhere, “bistable” variants, such as chromosome translocations, have two alternative stable frequencies, absence and (near) fixation. Analogous to populations with Allee effects, bistable variants tend to increase locally only once they become sufficiently common, and their spread depends on their rate of increase averaged over all frequencies. Several proposed manipulations of insect populations, such as using Wolbachia or “engineered underdominance” to suppress vector-borne diseases, produce bistable rather than Fisherian dynamics. We synthesize and extend theoretical analyses concerning three features of their spatial behavior: rate of spread, conditions to initiate spread from a localized introduction, and wave stopping caused by variation in population densities or dispersal rates. Unlike Fisherian variants, bistable variants tend to spread spatially only for particular parameter combinations and initial conditions. Wave initiation requires introduction over an extended region, while subsequent spatial spread is slower than for Fisherian waves and can easily be halted by local spatial inhomogeneities. We present several new results, including robust sufficient conditions to initiate (and stop) spread, using a one-parameter cubic approximation applicable to several models. The results have both basic and applied implications

Deploying dengue-suppressing Wolbachia: Robust models predict slow but effective spatial spread in Aedes aegypti

A novel strategy for controlling the spread of arboviral diseases such as dengue, Zika and chikungunya is to transform mosquito populations with virus-suppressing Wolbachia. In general, Wolbachia transinfected into mosquitoes induce fitness costs through lower viability or fecundity. These maternally inherited bacteria also produce a frequency-dependent advantage for infected females by inducing cytoplasmic incompatibility (CI), which kills the embryos produced by uninfected females mated to infected males. These competing effects, a frequency-dependent advantage and frequency-independent costs, produce bistable Wolbachia frequency dynamics. Above a threshold frequency, denoted pˆ, CI drives fitness-decreasing Wolbachia transinfections through local populations; but below pˆ, infection frequencies tend to decline to zero. If pˆ is not too high, CI also drives spatial spread once infections become established over sufficiently large areas. We illustrate how simple models provide testable predictions concerning the spatial and temporal dynamics of Wolbachia introductions, focusing on rate of spatial spread, the shape of spreading waves, and the conditions for initiating spread from local introductions. First, we consider the robustness of diffusion-based predictions to incorporating two important features of wMel-Aedes aegypti biology that may be inconsistent with the diffusion approximations, namely fast local dynamics induced by complete CI (i.e., all embryos produced from incompatible crosses die) and long-tailed, non-Gaussian dispersal. With complete CI, our numerical analyses show that long-tailed dispersal changes wave-width predictions only slightly; but it can significantly reduce wave speed relative to the diffusion prediction; it also allows smaller local introductions to initiate spatial spread. Second, we use approximations for pˆ and dispersal distances to predict the outcome of 2013 releases of wMel-infected Aedes aegypti in Cairns, Australia, Third, we describe new data from Ae. aegypti populations near Cairns, Australia that demonstrate long-distance dispersal and provide an approximate lower bound on pˆ for wMel in northeastern Australia. Finally, we apply our analyses to produce operational guidelines for efficient transformation of vector populations over large areas. We demonstrate that even very slow spatial spread, on the order of 10-20 m/month (as predicted), can produce area-wide population transformation within a few years following initial releases covering about 20-30% of the target area

Wolbachia in the Drosophila yakuba Complex: Pervasive Frequency Variation and Weak Cytoplasmic Incompatibility, but No Apparent Effect on Reproductive Isolation

Three hybridizing species—the clade [(Drosophila yakuba, D. santomea), D. teissieri]—comprise the yakuba complex in the D. melanogaster subgroup. Their ranges overlap on Bioko and São Tomé, islands off west Africa. All three species are infected with Wolbachia—maternally inherited, endosymbiotic bacteria, best known for manipulating host reproduction to favor infected females. Previous analyses reported no cytoplasmic incompatibility (CI) in these species. However, we discovered that Wolbachia from each species cause intraspecific and interspecific CI. In D. teissieri, analyses of F1 and backcross genotypes show that both host genotype and Wolbachia variation modulate CI intensity. Wolbachia-infected females seem largely protected from intraspecific and interspecific CI, irrespective of Wolbachia and host genotypes. Wolbachia do not affect host mating behavior or female fecundity, within or between species. The latter suggests little apparent effect of Wolbachia on premating or gametic reproductive isolation (RI) between host species. In nature, Wolbachia frequencies varied spatially for D. yakuba in 2009, with 76% (N = 155) infected on São Tomé, and only 3% (N = 36) infected on Bioko; frequencies also varied temporally in D. yakuba and D. santomea on São Tomé between 2009 and 2015. These temporal frequency fluctuations could generate asymmetries in interspecific mating success, and contribute to postzygotic RI. However, the fluctuations in Wolbachia frequencies that we observe also suggest that asymmetries are unlikely to persist. Finally, we address theoretical questions that our empirical findings raise about Wolbachia persistence when conditions fluctuate, and about the stable coexistence of Wolbachia and host variants that modulate Wolbachia effects

From Parasite to Mutualist: Rapid Evolution of Wolbachia in Natural Populations of Drosophila

Wolbachia are maternally inherited bacteria that commonly spread through host populations by causing cytoplasmic incompatibility, often expressed as reduced egg hatch when uninfected females mate with infected males. Infected females are frequently less fecund as a consequence of Wolbachia infection. However, theory predicts that because of maternal transmission, these “parasites” will tend to evolve towards a more mutualistic association with their hosts. Drosophila simulans in California provided the classic case of a Wolbachia infection spreading in nature. Cytoplasmic incompatibility allowed the infection to spread through individual populations within a few years and from southern to northern California (more than 700 km) within a decade, despite reducing the fecundity of infected females by 15%–20% under laboratory conditions. Here we show that the Wolbachia in California D. simulans have changed over the last 20 y so that infected females now exhibit an average 10% fecundity advantage over uninfected females in the laboratory. Our data suggest smaller but qualitatively similar changes in relative fecundity in nature and demonstrate that fecundity-increasing Wolbachia variants are currently polymorphic in natural populations

Loss of cytoplasmic incompatibility and minimal fecundity effects explain relatively low Wolbachia frequencies in Drosophila mauritiana

Maternally transmitted Wolbachia bacteria infect about half of all insect species. Many Wolbachia cause cytoplasmic incompatibility (CI) and reduced egg hatch when uninfected females mate with infected males. Although CI produces a frequency-dependent fitness advantage that leads to high equilibrium Wolbachia frequencies, it does not aid Wolbachia spread from low frequencies. Indeed, the fitness advantages that produce initial Wolbachia spread and maintain non-CI Wolbachia remain elusive. wMau Wolbachia infecting Drosophila mauritiana do not cause CI, despite being very similar to CI-causing wNo from Drosophila simulans (0.068% sequence divergence over 682,494 bp), suggesting recent CI loss. Using draft wMau genomes, we identify a deletion in a CI-associated gene, consistent with theory predicting that selection within host lineages does not act to increase or maintain CI. In the laboratory, wMau shows near-perfect maternal transmission; but we find no significant effect on host fecundity, in contrast to published data. Intermediate wMau frequencies on the island of Mauritius are consistent with a balance between unidentified small, positive fitness effects and imperfect maternal transmission. Our phylogenomic analyses suggest that group-B Wolbachia, including wMau and wPip, diverged from group-A Wolbachia, such as wMel and wRi, 6-46 million years ago, more recently than previously estimated