Scholarly Literature

This is a database of scholarly literature that concentrates currently on natural and engineered selfish genetic elements (gene drives).  The latest are shown here.
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Recommendations for Laboratory Containment and Management of Gene Drive Systems in Arthropods

4032
Benedict, MQB, Austin; Capurro, Margareth L.; De Barro, Paul; Handler, Alfred M.; Hayes, Keith R.; Marshall, John M.; Tabachnick, Walter J.; Adelman, Zach N.,  Vector-Borne and Zoonotic Diseases,  18:2-13. 2017-01-10 00:00:00.
Versatile molecular tools for creating driving transgenes and other invasive genetic factors present regulatory, ethical, and environmental challenges that should be addressed to ensure their safe use. In this article, we discuss driving transgenes and invasive genetic factors that can potentially spread after their introduction into a small proportion of individuals in a population. The potential of invasive genetic factors to increase their number in natural populations presents challenges that require additional safety measures not provided by previous recommendations regarding accidental release of arthropods. In addition to providing physical containment, invasive genetic factors require greater attention to strain management, including their distribution and identity confirmation. In this study, we focus on insects containing such factors with recommendations for investigators who are creating them, institutional biosafety committees charged with ensuring safety, funding agencies providing support, those managing insectaries handling these materials who are responsible for containment, and other persons who will be receiving insects?transgenic or not?from these facilities. We give specific examples of efforts to modify mosquitoes for mosquito-borne disease control, but similar considerations are relevant to other arthropods that are important to human health, the environment, and agriculture.; Versatile molecular tools for creating driving transgenes and other invasive genetic factors present regulatory, ethical, and environmental challenges that should be addressed to ensure their safe use. In this article, we discuss driving transgenes and invasive genetic factors that can potentially spread after their introduction into a small proportion of individuals in a population. The potential of invasive genetic factors to increase their number in natural populations presents challenges that require additional safety measures not provided by previous recommendations regarding accidental release of arthropods. In addition to providing physical containment, invasive genetic factors require greater attention to strain management, including their distribution and identity confirmation. In this study, we focus on insects containing such factors with recommendations for investigators who are creating them, institutional biosafety committees charged with ensuring safety, funding agencies providing support, those managing insectaries handling these materials who are responsible for containment, and other persons who will be receiving insects?transgenic or not?from these facilities. We give specific examples of efforts to modify mosquitoes for mosquito-borne disease control, but similar considerations are relevant to other arthropods that are important to human health, the environment, and agriculture.

X chromosome drive in a widespread Palearctic woodland fly, Drosophila testacea

4052
Keais, GLH, M. A.; Gowen, B. E.; Perlman, S. J.,  Journal of Evolutionary Biology,  30:1185-1194. 2017-01-10 00:00:00.
Selfish genes that bias their own transmission during meiosis can spread rapidly in populations, even if they contribute negatively to the fitness of their host. Driving X chromosomes provide a clear example of this type of selfish propagation. These chromosomes have important evolutionary and ecological consequences, and can be found in a broad range of taxa including plants, mammals and insects. Here, we report a new case of X chromosome drive (X drive) in a widespread woodland fly, Drosophila testacea. We show that males carrying the driving X (SR males) sire 80-100% female offspring and possess a diagnostic X chromosome haplotype that is perfectly associated with the sex ratio distortion phenotype. We find that the majority of sons produced by SR males are sterile and appear to lack a Y chromosome, suggesting that meiotic defects involving the Y chromosome may underlie X drive in this species. Abnormalities in sperm cysts of SR males reflect that some spermatids are failing to develop properly, confirming that drive is acting during gametogenesis. By screening wild-caught flies using progeny sex ratios and a diagnostic marker, we demonstrate that the driving X is present in wild populations at a frequency of similar to 10% and that suppressors of drive are segregating in the same population. The testacea species group appears to be a hot spot for X drive, and D. testacea is a promising model to compare driving X chromosomes in closely related species, some of which may even be younger than the chromosomes themselves.

Evaluating strategies for reversing CRISPR-Cas9 gene drives

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Vella, MRG, Christian E.; Lloyd, Alun L.; Gould, Fred,  Scientific Reports,  7:11038. 2017-01-09 00:00:00.
A gene drive biases inheritance of a gene so that it increases in frequency within a population even when the gene confers no fitness benefit. There has been renewed interest in environmental releases of engineered gene drives due to recent proof of principle experiments with the CRISPR-Cas9 system as a drive mechanism. Release of modified organisms, however, is controversial, especially when the drive mechanism could theoretically alter all individuals of a species. Thus, it is desirable to have countermeasures to reverse a drive if a problem arises. Several genetic mechanisms for limiting or eliminating gene drives have been proposed and/or developed, including synthetic resistance, reversal drives, and immunizing reversal drives. While predictions about efficacy of these mechanisms have been optimistic, we lack detailed analyses of their expected dynamics. We develop a discrete time model for population genetics of a drive and proposed genetic countermeasures. Efficacy of drive reversal varies between countermeasures. For some parameter values, the model predicts unexpected behavior including polymorphic equilibria and oscillatory dynamics. The timing and number of released individuals containing a genetic countermeasure can substantially impact outcomes. The choice among countermeasures by researchers and regulators will depend on specific goals and population parameters of target populations.

Requirements for Driving Antipathogen Effector Genes into Populations of Disease Vectors by Homing

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Beaghton, AH, Andrew; Nolan, Tony; Crisanti, Andrea; Godfray, H. Charles J.; Burt, Austin,  Genetics,  205:1587-1596. 2017-01-09 00:00:00.
There is a need for new interventions against the ongoing burden of vector-borne diseases such as malaria and dengue. One suggestion has been to develop genes encoding effector molecules that block parasite development within the vector, and then use the nuclease-based homing reaction as a form of gene drive to spread those genes through target populations. If the effector gene reduces the fitness of the mosquito and does not contribute to the drive, then loss-of-function mutations in the effector will eventually replace functional copies, but protection may nonetheless persist sufficiently long to provide a public health benefit. Here, we present a quantitative model allowing one to predict the duration of protection as a function of the probabilities of different molecular processes during the homing reaction, various fitness effects, and the efficacy of the effector in blocking transmission. Factors that increase the duration of protection include reducing the frequency of pre-existing resistant alleles, the probability of nonrecombinational DNA repair, the probability of homing-associated loss of the effector, the fitness costs of the nuclease and effector, and the completeness of parasite blocking. For target species that extend over an area much larger than the typical dispersal distance, the duration of protection is expected to be highest at the release site, and decrease away from there, eventually falling to zero, as effector-less drive constructs replace effector-containing ones. We also model an alternative strategy of using the nuclease to target an essential gene, and then linking the effector to a sequence that restores the essential function and is resistant to the nuclease. Depending upon parameter values, this approach can prolong the duration of protection. Our models highlight the key design criteria needed to achieve a desired level of public health benefit.%U http://www.genetics.org/content/genetics/205/4/1587.full.pdf

Sry gene drive for rodent control: Reply to Gemmell and Tompkins

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Kanavy, DS, M.,  Trends in Ecology & Evolution,  32:315-316. 2017-01-09 00:00:00.
We would like to thank Gemmell and Tompkins for their interest and comments onthe articlebyPiaggioet al. [1].Theissues raised by Gemmell and Tompkins [2] are very pertinent, and they correctly identified that the format of the article did not lend itself to a comprehensive discussion of the ideas of using gene drives in mice. The method being considered in the Piaggio et al. article is to utilize a naturally occurring t-allele transgene (Tg) to sex-bias amouse population, causing it to crash. Inserting the sex-determining region on the Y chromosome (Sry) into the Tg allows biased inheritance where the majority of the offspring born are phenotypically male.

Eradicating Mosquitoes? The promise and peril of gene drive technologies.

4050
Jun, B-O,  Eubios Journal of Asian and International Bioethics,  27:113-116. 2017-01-08 00:00:00.
This paper discusses the ethical issues associated with genetic modification of mosquito species that are human disease vectors. The Oxitec genetically changed mosquito—a variant of a species called Aedes aegypti, OX513A, is taken as an example. The benefits and risks are discussed, and questions need to be discussed in public prior to release of this gene drive system

Evolution of Resistance Against CRISPR/Cas9 Gene Drive

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Unckless, RLC, A. G.; Messer, P. W.,  Genetics,  205:827-841. 2017-01-08 00:00:00.
CRISPR/Cas9 gene drive (CGD) promises to be a highly adaptable approach for spreading genetically engineered alleles throughout a species, even if those alleles impair reproductive success. CGD has been shown to be effective in laboratory crosses of insects, yet it remains unclear to what extent potential resistance mechanisms will affect the dynamics of this process in large natural populations. Here we develop a comprehensive population genetic framework for modeling CGD dynamics, which incorporates potential resistance mechanisms as well as random genetic drift. Using this framework, we calculate the probability that resistance against CGD evolves from standing genetic variation, de novo mutation of wild-type alleles, or cleavage repair by nonhomologous end joining (NHEJ)-a likely by-product of CGD itself. We show that resistance to standard CGD approaches should evolve almost inevitably in most natural populations, unless repair of CGD-induced cleavage via NHEJ can be effectively suppressed, or resistance costs are on par with those of the driver. The key factor determining the probability that resistance evolves is the overall rate at which resistance alleles arise at the population level by mutation or NHEJ. By contrast, the conversion efficiency of the driver, its fitness cost, and its introduction frequency have only minor impact. Our results shed light on strategies that could facilitate the engineering of drivers with lower resistance potential, and motivate the possibility to embrace resistance as a possible mechanism for controlling a CGD approach. This study highlights the need for careful modeling of the population dynamics of CGD prior to the actual release of a driver construct into the wild.

Vector control with driving Y chromosomes: modelling the evolution of resistance

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Beaghton, AB, P. J.; Burt, A.,  Malaria Journal,  16:286. 2017-01-08 00:00:00.
: The introduction of new malaria control interventions has often led to the evolution of resistance, both of the parasite to new drugs and of the mosquito vector to new insecticides, compromising the efficacy of the interventions. Recent progress in molecular and population biology raises the possibility of new genetic-based interventions, and the potential for resistance to evolve against these should be considered. Here, population modelling is used to determine the main factors affecting the likelihood that resistance will evolve against a synthetic, nuclease-based driving Y chromosome that produces a male-biased sex ratio. Methods: A combination of deterministic differential equation models and stochastic analyses involving branching processes and Gillespie simulations is utilized to assess the probability that resistance evolves against a driving Y that otherwise is strong enough to eliminate the target population. The model considers resistance due to changes at the target site such that they are no longer cleaved by the nuclease, and due to trans-acting autosomal suppressor alleles. Results: The probability that resistance evolves increases with the mutation rate and the intrinsic rate of increase of the population, and decreases with the strength of drive and any pleiotropic fitness costs of the resistant allele. In seasonally varying environments, the time of release can also affect the probability of resistance evolving. Trans-acting suppressor alleles are more likely to suffer stochastic loss at low frequencies than target site resistant alleles. Conclusions: As with any other intervention, there is a risk that resistance will evolve to new genetic approaches to vector control, and steps should be taken to minimize this probability. Two design features that should help in this regard are to reduce the rate at which resistant mutations arise, and to target sequences such that if they do arise, they impose a significant fitness cost on the mosquito.

A large gene family in fission yeast encodes spore killers that subvert Mendel’s law

4049
Hu, WJ, Z. D.; Suo, F.; Zheng, J. X.; He, W. Z.; Du, L. L.,  eLife,  6:e28567. 2017-01-07 00:00:00.
Spore killers in fungi are selfish genetic elements that distort Mendelian segregation in their favor. It remains unclear how many species harbor them and how diverse their mechanisms are. Here, we discover two spore killers from a natural isolate of the fission yeast Schizosaccharomyces pombe. Both killers belong to the previously uncharacterized wtf gene family with 25 members in the reference genome. These two killers act in strain-background-independent and genome-location-independent manners to perturb the maturation of spores not inheriting them. Spores carrying one killer are protected from its killing effect but not that of the other killer. The killing and protecting activities can be uncoupled by mutation. The numbers and sequences of wtf genes vary considerably between S. pombe isolates, indicating rapid divergence. We propose that wtf genes contribute to the extensive intraspecific reproductive isolation in S. pombe, and represent ideal models for understanding how segregation-distorting elements act and evolve.

New Weapons in the Toad Toolkit: A Review of Methods to Control and Mitigate the Biodiversity Impacts of Invasive Cane Toads (Rhinella Marina)

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Tingley, RW-F, Georgia; Schwarzkopf, Lin; Greenlees, Matthew J.; Phillips, Benjamin L.; Brown, Gregory; Clulow, Simon; Webb, Jonathan; Capon, Robert; Sheppard, Andy; Strive, Tanja; Tizard, Mark; Shine, Richard,  The Quarterly Review of Biology,  92:123-149. 2017-01-07 00:00:00.
Our best hope of developing innovative methods to combat invasive species is likely to come from the study of high-profile invaders that have attracted intensive research not only into control, but also basic biology. Here we illustrate that point by reviewing current thinking about novel ways to control one of the world?s most well-studied invasions: that of the cane toad in Australia. Recently developed methods for population suppression include more effective traps based on the toad?s acoustic and pheromonal biology. New tools for containing spread include surveillance technologies (e.g., eDNA sampling and automated call detectors), as well as landscape-level barriers that exploit the toad?s vulnerability to desiccation?a strategy that could be significantly enhanced through the introduction of sedentary, range-core genotypes ahead of the invasion front. New methods to reduce the ecological impacts of toads include conditioned taste aversion in free-ranging predators, gene banking, and targeted gene flow. Lastly, recent advances in gene editing and gene drive technology hold the promise of modifying toad phenotypes in ways that may facilitate control or buffer impact. Synergies between these approaches hold great promise for novel and more effective means to combat the toad invasion and its consequent impacts on biodiversity.

B Chromosomes – A matter of chromosome drive

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Houben, A,  Frontiers in Plant Science,  8:210. 2017-01-06 00:00:00.
B chromosomes are supernumerary chromosomes which are often preferentially inherited, deviating from usual Mendelian segregation. The balance between the so-called chromosome drive and the negative effects that the presence of Bs applies on the fitness of their host determines the frequency of Bs in a particular population. Drive is the key for understanding most B chromosomes. Drive occurs in many ways at pre-meiotic, meiotic or post-meiotic divisions, but the molecular mechanism remains unclear. The cellular mechanism of drive is reviewed based on the findings obtained for the B chromosomes of rye, maize and other species. How novel analytical tools will expand our ability to uncover the biology of B chromosome drive is discussed.

Spatial gene drives and pushed genetic waves

4068
Tanaka, HS, Howard A.; Nelson, David R.,  Proceedings of the National Academy of Sciences of the United States of America,  114:8452. 2017-01-06 00:00:00.
Gene constructs introduced into natural environments have been proposed to solve various ecological problems. The CRISPR-Cas9 technology greatly facilitates construction of gene drives that allow desired traits to rapidly replace wild types, even if these convey a selective growth rate disadvantage s > 0. However, accidental release of a gene drive could damage ecosystems irreversibly. We have modeled the spatial spread of gene drives and find a preferred range of selective disadvantages, 0.5 < s < 0.697. In this regime, gene drives spread but only when a nucleus exceeds a critical size and intensity. By making gene drives uniquely susceptible to a compound, their advance can be stopped in two dimensions by finite-width barriers, even when interrupted by gaps.Gene drives have the potential to rapidly replace a harmful wild-type allele with a gene drive allele engineered to have desired functionalities. However, an accidental or premature release of a gene drive construct to the natural environment could damage an ecosystem irreversibly. Thus, it is important to understand the spatiotemporal consequences of the super-Mendelian population genetics before potential applications. Here, we use a reaction–diffusion model for sexually reproducing diploid organisms to study how a locally introduced gene drive allele spreads to replace the wild-type allele, although it possesses a selective disadvantage s > 0. Using methods developed by Barton and collaborators, we show that socially responsible gene drives require 0.5 < s < 0.697, a rather narrow range. In this “pushed wave” regime, the spatial spreading of gene drives will be initiated only when the initial frequency distribution is above a threshold profile called “critical propagule,” which acts as a safeguard against accidental release. We also study how the spatial spread of the pushed wave can be stopped by making gene drives uniquely vulnerable (“sensitizing drive”) in a way that is harmless for a wild-type allele. Finally, we show that appropriately sensitized drives in two dimensions can be stopped, even by imperfect barriers perforated by a series of gaps.

Towards the genetic control of invasive species

4047
Harvey-Samuel, TA, T.; Alphey, L.,  Biological Invasions,  19:1683-1703. 2017-01-05 00:00:00.
Invasive species remain one of the greatest threats to global biodiversity. Their control would be enhanced through the development of more effective and sustainable pest management strategies. Recently, a novel form of genetic pest management (GPM) has been developed in which the mating behaviour of insect pests is exploited to introduce genetically engineered DNA sequences into wild conspecific populations. These 'transgenes' work in one or more ways to reduce the damage caused by a particular pest, for example reducing its density, or its ability to vector disease. Although currently being developed for use against economically important insect pests, these technologies would be highly appropriate for application against invasive species that threaten biodiversity. Importantly, these technologies have begun to advance in scope beyond insects to vertebrates, which include some of the world's worst invasives. Here we review the current state of this rapidly progressing field and, using an established set of eradication criteria, discuss the characteristics which make GPM technologies suitable for application against invasive pests.

Results from the Workshop “Problem Formulation for the Use of Gene Drive in Mosquitoes”

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Roberts, ADA, P. P.; Okumu, F.; Quemada, H.; Savadogo, M.; Singh, J. A.; James, S.,  American Journal of Tropical Medicine and Hygiene,  96:530-533. 2017-01-04 00:00:00.
Reducing the incidence of malaria has been a public health priority for nearly a century. New technologies and associated vector control strategies play an important role in the prospect of sustained reductions. The development of the CRISPR/Cas9 gene editing system has generated new possibilities for the use of gene-drive constructs to reduce or alter vector populations to reduce malaria incidence. However, before these technologies can be developed and exploited, it will be necessary to understand and assess the likelihood of any potential harms to humans or the environment. To begin this process, the Foundation for the National Institutes of Health and the International Life Sciences Institute Research Foundation organized an expert workshop to consider the potential risks related to the use of gene drives in Anopheles gambiae for malaria control in Africa. The resulting discussion yielded a series of consensus points that are reported here.

The creation and selection of mutations resistant to a gene drive over multiple generations in the malaria mosquito

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Hammond, AMK, Kyros; Bruttini, Marco; North, Ace; Galizi, Roberto; Karlsson, Xenia; Kranjc, Nace; Carpi, Francesco M.; D’Aurizio, Romina; Crisanti, Andrea; Nolan, Tony,  PLOS Genetics,  13:e1007039. 2017-01-04 00:00:00.
Gene drives are selfish genetic elements that are able to bias their own inheritance among offspring. Starting from very low frequencies they can rapidly invade a population in just a few generations, even when imposing a fitness cost. Gene drives based on the precise DNA cutting enzyme CRISPR have been shown recently to be highly efficient at copying themselves from one chromosome to the other during the process of gamete formation in mosquitoes, resulting in transmission to 99% of offspring instead of the 50% expected for a single gene copy. One proposed use for CRISPR-based gene drives is in the control of mosquitoes by designing the gene drive to target mosquito genes involved in fertility, thereby reducing their overall reproductive output and leading to population suppression. Like any intervention designed to suppress a population these gene drives are expected to select for mutations in the mosquito that are resistant to the drive and restore fertility to mosquitoes. We have analyzed the origin and selection of resistant alleles in caged populations of mosquitoes initiated with a gene drive construct targeting a female fertility gene. We find the selected alleles are in-frame insertions and deletions that are resistant to cleavage and restore female fertility. Our findings allow us to improve predictions on gene drive behaviour and to make concrete recommendations on how to improve future gene drive designs by decreasing the likelihood that they generate resistance.

Advances in vector control science: Rear-and-release strategies show promise… but don’t forget the basics

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Ritchie, SAJ, B. J.,  Journal of Infectious Diseases,  215:S103-S108. 2017-01-03 00:00:00.
Both chikungunya and Zika viruses have recently swept from Africa across the Pacific to the Americas, causing major outbreaks of disease in humans. In the meantime, dengue epidemics continue throughout the tropics. Traditional vector control programs based on strategies from 1950s and 1960s have been relatively ineffective in combating recent epidemics. In response, new methods involving the rearing and releasing of large numbers of mosquitoes to eliminate or modify local Aedes populations are being developed, with several currently conducting field releases in high-risk countries. These advances, include the release of Wolbachia-infected Aedes aegypti and Aedes albopictus, for either its virus-blocking capabilities, sterilization by cytoplasmic incompatibility, or both; the release of Aedes carrying dominant lethal genes, such as the OX513A strain of A. aegypti; and other emerging techniques, such as advancing gene-drive technologies, are summarized, as well as current stages of development and primary operational and regulatory hurdles. Although these technologies show great promise, none are ready for widespread rollout for cities of millions of people. Thus, efforts should be made to avoid methods such as space sprays that have failed and improve existing technologies to increase their efficacy.

CRISPR-based gene drive in agriculture will face technical and governance challenges

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Gutzmann, NE, Johanna E.; Barnes, Jessica Cavin; Baltzegar, Jennifer; Jones, Michael S.; Sudweeks, Jayce,  EMBO reports,  18:1479-1480. 2017-01-03 00:00:00.
Comment on "Agricultural pest control with CRISPR-based gene drive: time for public debate" by Courtier-Orgogozo et al.

CRISPR/Cas9 gene drive: Growing pains for a new technology

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Reed, FA,  Genetics,  205:1037-1039. 2017-01-02 00:00:00.
In this commentary, Floyd Reed discusses Unckless et al. (2017),; “Evolution of resistance against CRISPR/Cas9 gene drive,”; which was published in the February issue of GENETICS.

Potential of gene drives with genome editing to increase genetic gain in livestock breeding programs

4044
Gonen, SJ, J.; Gorjanc, G.; Mileham, A. J.; Whitelaw, C. B. A.; Hickey, J. M.,  Genetics Selection Evolution,  49:14. 2017-01-02 00:00:00.
This paper uses simulation to explore how gene drives can increase genetic gain in livestock breeding programs. Gene drives are naturally occurring phenomena that cause a mutation on one chromosome to copy itself onto its homologous chromosome. Methods: We simulated nine different breeding and editing scenarios with a common overall structure. Each scenario began with 21 generations of selection, followed by 20 generations of selection based on true breeding values where the breeder used selection alone, selection in combination with genome editing, or selection with genome editing and gene drives. In the scenarios that used gene drives, we varied the probability of successfully incorporating the gene drive. For each scenario, we evaluated genetic gain, genetic variance (sigma(2)(A)), rate of change in inbreeding (Delta F), number of distinct quantitative trait nucleotides (QTN) edited, rate of increase in favourable allele frequencies of edited QTN and the time to fix favourable alleles. Results: Gene drives enhanced the benefits of genome editing in seven ways: (1) they amplified the increase in genetic gain brought about by genome editing; (2) they amplified the rate of increase in the frequency of favourable alleles and reduced the time it took to fix them; (3) they enabled more rapid targeting of QTN with lesser effect for genome editing; (4) they distributed fixed editing resources across a larger number of distinct QTN across generations; (5) they focussed editing on a smaller number of QTN within a given generation; (6) they reduced the level of inbreeding when editing a subset of the sires; and (7) they increased the efficiency of converting genetic variation into genetic gain. Conclusions: Genome editing in livestock breeding results in short-, medium- and long-term increases in genetic gain. The increase in genetic gain occurs because editing increases the frequency of favourable alleles in the population. Gene drives accelerate the increase in allele frequency caused by editing, which results in even higher genetic gain over a shorter period of time with no impact on inbreeding.

The End of the GMO? Genome Editing, Gene Drives and New Frontiers of Plant Technology

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K. L. Hefferon and R. J. Herring,  Review of Agrarian Studies,  7. 2017-01-01 21:40:33.
mprovements to agriculture will constitute one of the world’s greatest challenges in the coming century. Political and social controversies, as well as complications of plant breeding, intellectual property, and regulation, have compromised the promised impact of genetically engineered – typically transgenic – crops designated as “GMOs.” Genome editing is a new suite of molecular tools for assisting biologists identify genes that control agronomic traits such as drought tolerance and pest resistance, as well as to elucidate how expression of these genes is intertwined within the functional framework of the cell. This technology has recently gained momentum for its ability to accelerate the crop breeding process in an unprecedented fashion and expand the range of crop varieties with improved precision and lower costs. This review explains the basic concepts and provides examples of how genome editing could help address the United Nation’s Sustainable Development Goals with respect to food, agriculture, and medicine. It concludes with a discussion of the potential social impact of genome editing and gene drive. These effects are contingent on the resolution of novel ethical and regulatory challenges that add new layers of complexity to societal questions of appropriate technology, in agriculture and beyond. We expect these questions to replace the irresolvable GMO debate.

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