Imperial College London

ProfessorAustinBurt

Faculty of Natural SciencesDepartment of Life Sciences (Silwood Park)

Professor of Evolutionary Genetics
 
 
 
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Contact

 

+44 (0)20 7594 2266a.burt

 
 
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Location

 

Silwood ParkSilwood Park

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Summary

 

Publications

Publication Type
Year
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114 results found

Connolly JB, Mumford JD, Fuchs S, Turner G, Beech C, North AR, Burt Aet al., 2021, Systematic identification of plausible pathways to potential harm via problem formulation for investigational releases of a population suppression gene drive to control the human malaria vector Anopheles gambiae in West Africa., Malar J, Vol: 20

BACKGROUND: Population suppression gene drive has been proposed as a strategy for malaria vector control. A CRISPR-Cas9-based transgene homing at the doublesex locus (dsxFCRISPRh) has recently been shown to increase rapidly in frequency in, and suppress, caged laboratory populations of the malaria mosquito vector Anopheles gambiae. Here, problem formulation, an initial step in environmental risk assessment (ERA), was performed for simulated field releases of the dsxFCRISPRh transgene in West Africa. METHODS: Building on consultative workshops in Africa that previously identified relevant environmental and health protection goals for ERA of gene drive in malaria vector control, 8 potentially harmful effects from these simulated releases were identified. These were stratified into 46 plausible pathways describing the causal chain of events that would be required for potential harms to occur. Risk hypotheses to interrogate critical steps in each pathway, and an analysis plan involving experiments, modelling and literature review to test each of those risk hypotheses, were developed. RESULTS: Most potential harms involved increased human (n = 13) or animal (n = 13) disease transmission, emphasizing the importance to subsequent stages of ERA of data on vectorial capacity comparing transgenics to non-transgenics. Although some of the pathways (n = 14) were based on known anatomical alterations in dsxFCRISPRh homozygotes, many could also be applicable to field releases of a range of other transgenic strains of mosquito (n = 18). In addition to population suppression of target organisms being an accepted outcome for existing vector control programmes, these investigations also revealed that the efficacy of population suppression caused by the dsxFCRISPRh transgene should itself directly affect most pathways (n = 35). CONCLUSIONS: Modelling will play an essential role in subsequent stages of ERA by clarify

Journal article

O'Loughlin SM, Forster AJ, Fuchs S, Dottorini T, Nolan T, Crisanti A, Burt Aet al., 2021, Ultra-conserved sequences in the genomes of highly diverse Anopheles mosquitoes, with implications for malaria vector control., G3 (Bethesda)

DNA sequences that are exactly conserved over long evolutionary time scales have been observed in a variety of taxa. Such sequences are likely under strong functional constraint and they have been useful in the field of comparative genomics for identifying genome regions with regulatory function. A potential new application for these ultra-conserved elements has emerged in the development of gene drives to control mosquito populations. Many gene drives work by recognising and inserting at a specific target sequence in the genome, often imposing a reproductive load as a consequence. They can therefore select for target sequence variants that provide resistance to the drive. Focusing on highly conserved, highly constrained sequences lowers the probability that variant, gene drive-resistant alleles can be tolerated. Here we search for conserved sequences of 18bp and over in an alignment of 21 Anopheles genomes, spanning an evolutionary timescale of 100 million years, and characterise the resulting sequences according to their location and function. Over 8000 ultra-conserved elements were found across the alignment, with a maximum length of 164 bp. Length-corrected gene ontology analysis revealed that genes containing Anopheles ultra-conserved elements were over-represented in categories with structural or nucleotide binding functions. Known insect transcription factor binding sites were found in 48% of intergenic Anopheles ultra-conserved elements. When we looked at the genome sequences of 1142 wild-caught mosquitoes we found that 15% of the Anopheles ultra-conserved elements contained no polymorphisms. Our list of Anopheles ultra-conserved elements should provide a valuable starting point for the selection and testing of new targets for gene-drive modification in the mosquitoes that transmit malaria.

Journal article

Willis K, Burt A, 2021, Double drives and private alleles for localised population genetic control., PLoS Genet, Vol: 17

Synthetic gene drive constructs could, in principle, provide the basis for highly efficient interventions to control disease vectors and other pest species. This efficiency derives in part from leveraging natural processes of dispersal and gene flow to spread the construct and its impacts from one population to another. However, sometimes (for example, with invasive species) only specific populations are in need of control, and impacts on non-target populations would be undesirable. Many gene drive designs use nucleases that recognise and cleave specific genomic sequences, and one way to restrict their spread would be to exploit sequence differences between target and non-target populations. In this paper we propose and model a series of low threshold double drive designs for population suppression, each consisting of two constructs, one imposing a reproductive load on the population and the other inserted into a differentiated locus and controlling the drive of the first. Simple deterministic, discrete-generation computer simulations are used to assess the alternative designs. We find that the simplest double drive designs are significantly more robust to pre-existing cleavage resistance at the differentiated locus than single drive designs, and that more complex designs incorporating sex ratio distortion can be more efficient still, even allowing for successful control when the differentiated locus is neutral and there is up to 50% pre-existing resistance in the target population. Similar designs can also be used for population replacement, with similar benefits. A population genomic analysis of CRISPR PAM sites in island and mainland populations of the malaria mosquito Anopheles gambiae indicates that the differentiation needed for our methods to work can exist in nature. Double drives should be considered when efficient but localised population genetic control is needed and there is some genetic differentiation between target and non-target populations.

Journal article

Kemp L, Aldridge DC, Booy O, Bower H, Browne D, Burgmann M, Burt A, Cunningham AA, Dando M, Dick JTA, Dye C, Evans SW, Gallardo B, Godfray HCJ, Goodfellow I, Gubbins S, Holt LA, Jones KE, Kandil H, Martin P, McCaughan M, McLeish C, Meany T, Millett K, OhEigeartaigh SS, Patron NJ, Rhodes C, Roy HE, Shackelford G, Smith D, Spence N, Steiner H, Sundaram LS, Voeneky S, Walker JR, Watkins H, Whitby S, Wood J, Sutherland WJet al., 2021, 80 questions for UK biological security, PLOS ONE, Vol: 16, ISSN: 1932-6203

Journal article

Hammond A, Karlsson X, Morianou I, Kyrou K, Beaghton A, Gribble M, Kranjc N, Galizi R, Burt A, Crisanti A, Nolan Tet al., 2021, Regulating the expression of gene drives is key to increasing their invasive potential and the mitigation of resistance, PLOS GENETICS, Vol: 17, ISSN: 1553-7404

Journal article

Clarkson CS, Miles A, Harding NJ, Lucas ER, Battey CJ, Amaya-Romero JE, Kern AD, Fontaine MC, Donnelly MJ, Lawniczak MKN, Kwiatkowski DP, Donnelly MJ, Ayala D, Besansky NJ, Burt A, Caputo B, della Torre A, Fontaine MC, Godfray HCJ, Hahn MW, Kern AD, Kwiatkowski DP, Lawniczak MKN, Midega J, O'Loughlin S, Pinto J, Riehle MM, Sharakhov I, Schrider DR, Vernick KD, Weetman D, Wilding CS, White BJ, Troco AD, Pinto J, Cano J, Diabate A, Burt A, Costantini C, Rohatgi KR, Besansky NJ, Constant E, Weetman D, Elissa N, Nwakanma DC, Jawara M, Essandoh J, Coulibaly B, Riehle MM, Vernick KD, Dinis J, Midega J, Mbogo C, Bejon P, Le Goff G, Robert V, Wilding CS, Mawejje HD, Donnelly MJ, Stalker J, Rockett KA, Drury E, Mead D, Jeffreys AE, Hubbart C, Rowlands K, Isaacs AT, Jyothi D, Malangone C, Kamali Met al., 2020, Genome variation and population structure among 1142 mosquitoes of the African malaria vector species Anopheles gambiae and Anopheles coluzzii, GENOME RESEARCH, Vol: 30, Pages: 1533-1546, ISSN: 1088-9051

Journal article

Simoni A, Hammond AM, Beaghton AK, Galizi R, Taxiarchi C, Kyrou K, Meacci D, Gribble M, Morselli G, Burt A, Nolan T, Crisanti Aet al., 2020, A male-biased sex-distorter gene drive for the human malaria vector Anopheles gambiae, Nature Biotechnology, Vol: 38, Pages: 1054-1060, ISSN: 1087-0156

Only female insects transmit diseases such as malaria, dengue and Zika; therefore, control methods that bias the sex ratio of insect offspring have long been sought. Genetic elements such as sex-chromosome drives can distort sex ratios to produce unisex populations that eventually collapse, but the underlying molecular mechanisms are unknown. We report a male-biased sex-distorter gene drive (SDGD) in the human malaria vector Anopheles gambiae. We induced super-Mendelian inheritance of the X-chromosome-shredding I-PpoI nuclease by coupling this to a CRISPR-based gene drive inserted into a conserved sequence of the doublesex (dsx) gene. In modeling of invasion dynamics, SDGD was predicted to have a quicker impact on female mosquito populations than previously developed gene drives targeting female fertility. The SDGD at the dsx locus led to a male-only population from a 2.5% starting allelic frequency in 10-14 generations, with population collapse and no selection for resistance. Our results support the use of SDGD for malaria vector control.

Journal article

North AR, Burt A, Godfray HCJ, 2020, Modelling the suppression of a malaria vector using a CRISPR-Cas9 gene drive to reduce female fertility, BMC Biology, Vol: 18, ISSN: 1741-7007

BACKGROUND: Gene drives based on CRISPR-Cas9 technology are increasingly being considered as tools for reducing the capacity of mosquito populations to transmit malaria, and one of the most promising options is driving endonuclease genes that reduce the fertility of female mosquitoes. In particular, there is much interest in constructs that target the conserved mosquito doublesex (dsx) gene such that the emergence of functional drive-resistant alleles is unlikely. Proof of principle that these constructs can lead to substantial population suppression has been obtained in population cages, and they are being evaluated for use in sub-Saharan Africa. Here, we use simulation modelling to understand the factors affecting the spread of this type of gene drive over a one million-square kilometre area of West Africa containing substantial environmental and social heterogeneity. RESULTS: We found that a driving endonuclease gene targeting female fertility could lead to substantial reductions in malaria vector populations on a regional scale. The exact level of suppression is influenced by additional fitness costs of the transgene such as the somatic expression of Cas9, and its deposition in sperm or eggs leading to damage to the zygote. In the absence of these costs, or of emergent drive-resistant alleles that restore female fertility, population suppression across the study area is predicted to stabilise at ~ 95% 4 years after releases commence. Small additional fitness costs do not greatly affect levels of suppression, though if the fertility of females whose offspring transmit the construct drops by more than ~ 40%, then population suppression is much less efficient. We show the suppression potential of a drive allele with high fitness costs can be enhanced by engineering it also to express male bias in the progeny of transgenic males. Irrespective of the strength of the drive allele, the spatial model predicts somewhat less suppression than equivalent

Journal article

Simoni A, Hammond AM, Beaghton AK, Galizi R, Taxiarchi C, Kyrou K, Meacci D, Gribble M, Morselli G, Burt A, Nolan T, Crisanti Aet al., 2020, A male-biased sex-distorter gene drive for the human malaria vector Anopheles gambiae (vol 14, pg 931, 2020), NATURE BIOTECHNOLOGY, Vol: 38, Pages: 1097-1097, ISSN: 1087-0156

Journal article

Koufopanou V, Lomas S, Pronina O, Almeida P, Sampaio JP, Mousseau T, Liti G, Burt A, Piganeau Get al., 2020, Population Size, Sex and Purifying Selection: Comparative Genomics of Two Sister Taxa of the Wild Yeast Saccharomyces paradoxus, Genome biology and evolution, Vol: 12, Pages: 1636-1645, ISSN: 1759-6653

Abstract This study uses population genomic data to estimate demographic and selection parameters in two sister lineages of the wild yeast Saccharomyces paradoxus and compare their evolution. We first estimate nucleotide and recombinational diversities in each of the two lineages to infer their population size and frequency of sex and then analyze the rate of mutation accumulation since divergence from their inferred common ancestor to estimate the generation time and efficacy of selection. We find that one of the lineages has significantly higher silent nucleotide diversity and lower linkage disequilibrium, indicating a larger population with more frequent sexual generations. The same lineage also shows shorter generation time and higher efficacy of purifying selection, the latter consistent with the finding of larger population size and more frequent sex. Similar analyses are also performed on the ancestries of individual strains within lineages and we find significant differences between strains implying variation in rates of mitotic cell divisions. Our sample includes some strains originating in the Chernobyl nuclear-accident exclusion zone, which has been subjected to high levels of radiation for nearly 30 years now. We find no evidence, however, for increased rates of mutation. Finally, there is a positive correlation between rates of mutation accumulation and length of growing period, as measured by latitude of the place of origin of strains. Our study illustrates the power of genomic analyses in estimating population and life history parameters and testing predictions based on population genetic theory.

Journal article

Koufopanou V, 2020, Population size, sex and purifying selection: comparative genomics of two sister taxa of the wild yeast Saccharomyces paradoxus, Genome Biology and Evolution, Vol: 12, Pages: 1636-1645, ISSN: 1759-6653

This study uses population genomic data to estimate demographic and selection parameters in two sister lineages of the wild yeast Saccharomyces paradoxus and compare their evolution. We first estimate nucleotide and recombinational diversities in each of the two lineages to infer their population size and frequency of sex and then analyze the rate of mutation accumulation since divergence from their inferred common ancestor to estimate the generation time and efficacy of selection. We find that one of the lineages has significantly higher silent nucleotide diversity and lower linkage disequilibrium, indicating a larger population with more frequent sexual generations. The same lineage also shows shorter generation time and higher efficacy of purifying selection, the latter consistent with the finding of larger population size and more frequent sex. Similar analyses are also performed on the ancestries of individual strains within lineages and we find significant differences between strains implying variation in rates of mitotic cell divisions. Our sample includes some strains originating in the Chernobyl nuclear-accident exclusion zone, which has been subjected to high levels of radiation for nearly 30 years now. We find no evidence, however, for increased rates of mutation. Finally, there is a positive correlation between rates of mutation accumulation and length of growing period, as measured by latitude of the place of origin of strains. Our study illustrates the power of genomic analyses in estimating population and life history parameters and testing predictions based on population genetic theory.

Journal article

Hui T-YJ, Burt A, 2020, Estimating linkage disequilibrium from genotypes under Hardy-Weinberg equilibrium, BMC Genetics, Vol: 21, ISSN: 1471-2156

BACKGROUND: Measures of linkage disequilibrium (LD) play a key role in a wide range of applications from disease association to demographic history estimation. The true population LD cannot be measured directly and instead can only be inferred from genetic samples, which are unavoidably subject to measurement error. Previous studies of r2 (a measure of LD), such as the bias due to finite sample size and its variance, were based on the special case that the true population-wise LD is zero. These results generally do not hold for non-zero [Formula: see text] values, which are more common in real genetic data. RESULTS: This work generalises the estimation of r2 to all levels of LD, and for both phased and unphased data. First, we provide new formulae for the effect of finite sample size on the observed r2 values. Second, we find a new empirical formula for the variance of the observed r2, equals to 2E[r2](1 - E[r2])/n, where n is the diploid sample size. Third, we propose a new routine, Constrained ML, a likelihood-based method to directly estimate haplotype frequencies and r2 from diploid genotypes under Hardy-Weinberg Equilibrium. While serving the same purpose as the pre-existing Expectation-Maximisation algorithm, the new routine can have better convergence and is simpler to use. A new likelihood-ratio test is also introduced to test for the absence of a particular haplotype. Extensive simulations are run to support these findings. CONCLUSION: Most inferences on LD will benefit from our new findings, from point and interval estimation to hypothesis testing. Genetic analyses utilising r2 information will become more accurate as a result.

Journal article

Beaghton AK, Hammond A, Nolan T, Crisanti A, Burt Aet al., 2019, Gene drive for population genetic control: non-functional resistance and parental effects, Proceedings of the Royal Society B: Biological Sciences, Vol: 286, Pages: 1-8, ISSN: 0962-8452

Gene drive is a natural process of biased inheritance that, in principle, could be used to control pest and vector populations. As with any form of pest control, attention should be paid to the possibility of resistance evolving. For nuclease-based gene drive aimed at suppressing a population, resistance could arise by changes in the target sequence that maintain function, and various strategies have been proposed to reduce the likelihood that such alleles arise. Even if these strategies are successful, it is almost inevitable that alleles will arise at the target site that are resistant to the drive but do not restore function, and the impact of such sequences on the dynamics of control has been little studied. We use population genetic modelling of a strategy targeting a female fertility gene to demonstrate that such alleles may be expected to accumulate, and thereby reduce the reproductive load on the population, if nuclease expression per se causes substantial heterozygote fitness effects or if parental (especially paternal) deposition of nuclease either reduces offspring fitness or affects the genotype of their germline. All these phenomena have been observed in synthetic drive constructs. It will, therefore, be important to allow for non-functional resistance alleles in predicting the dynamics of constructs in cage populations and the impacts of any field release.

Journal article

Brown P, Tan A-C, El-Esawi MA, Liehr T, Blanck O, Gladue DP, Almeida GMF, Cernava T, Sorzano CO, Yeung AWK, Engel MS, Chandrasekaran AR, Muth T, Staege MS, Daulatabad SV, Widera D, Zhang J, Meule A, Honjo K, Pourret O, Yin C-C, Zhang Z, Cascella M, Flegel WA, Goodyear CS, van Raaij MJ, Bukowy-Bieryllo Z, Campana LG, Kurniawan NA, Lalaouna D, Huttner FJ, Ammerman BA, Ehret F, Cobine PA, Tan E-C, Han H, Xia W, McCrum C, Dings RPM, Marinello F, Nilsson H, Nixon B, Voskarides K, Yang L, Costa VD, Bengtsson-Palme J, Bradshaw W, Grimm DG, Kumar N, Martis E, Prieto D, Sabnis SC, Amer SEDR, Liew AWC, Perco P, Rahimi F, Riva G, Zhang C, Devkota HP, Ogami K, Basharat Z, Fierz W, Siebers R, Tan K-H, Boehme KA, Brenneisen P, Brown JAL, Dalrymple BP, Harvey DJ, Ng G, Werten S, Bleackley M, Dai Z, Dhariwal R, Gelfer Y, Hartmann MD, Miotla P, Tamaian R, Govender P, Gurney-Champion OJ, Kauppila JH, Zhang X, Echeverria N, Subhash S, Sallmon H, Tofani M, Bae T, Bosch O, Cuiv PO, Danchin A, Diouf B, Eerola T, Evangelou E, Filipp FV, Klump H, Kurgan L, Smith SS, Terrier O, Tuttle N, Ascher DB, Janga SC, Schulte LN, Becker D, Browngardt C, Bush SJ, Gaullier G, Ide K, Meseko C, Werner GDA, Zaucha J, Al-Farha AA, Greenwald NF, Popoola SI, Rahman MS, Xu J, Yang SY, Hiroi N, Alper OM, Baker CI, Bitzer M, Chacko G, Debrabant B, Dixon R, Forano E, Gilliham M, Kelly S, Klempnauer K-H, Lidbury BA, Lin MZ, Lynch I, Ma W, Maibach EW, Mather DE, Nandakumar KS, Ohgami RS, Parchi P, Tressoldi P, Xue Y, Armitage C, Barraud P, Chatzitheochari S, Coelho LP, Diao J, Doxey AC, Gobet A, Hu P, Kaiser S, Mitchell KM, Salama MF, Shabalin IG, Song H, Stevanovic D, Yadollahpour A, Zeng E, Zinke K, Alimba CG, Beyene TJ, Cao Z, Chan SS, Gatchell M, Kleppe A, Piotrowski M, Torga G, Woldesemayat AA, Cosacak MI, Haston S, Ross SA, Williams R, Wong A, Abramowitz MK, Effiong A, Lee S, Abid MB, Agarabi C, Alaux C, Albrecht DR, Atkins GJ, Beck CR, Bonvin AMJJ, Bourke E, Brand T, Braun RJ, Bull JA, Cardoso P, Carter Det al., 2019, Large expert-curated database for benchmarking document similarity detection in biomedical literature search, Database: the journal of biological databases and curation, Vol: 2019, Pages: 1-66, ISSN: 1758-0463

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.

Journal article

Khatri BS, Burt A, 2019, Robust estimation of recent effective population size from number of independent origins in soft sweeps, Molecular Biology and Evolution, Vol: 36, Pages: 2040-2052, ISSN: 1537-1719

Estimating recent effective population size is of great importance in characterising and predicting the evolution of natural populations. Methods based on nucleotide diversity may underestimate current day effective population sizes due to historical bottlenecks, whilst methods that reconstruct demographic history typically only detect long-term variations. However, soft selective sweeps, which leave a fingerprint of mutational history by recurrent mutations on independent haplotype backgrounds, holds promise of an estimate more representative of recent population history. Here we present a simple and robust method of estimation based only on knowledge of the number of independent recurrent origins and the current frequency of the beneficial allele in a population sample, independent of the strength of selection and age of the mutation. Using a forward time theoretical framework, we show the mean number of origins is a function of θ=2Nμ and current allele frequency, through a simple equation, and the distribution is approximately Poisson. This estimate is robust to whether mutants pre-existed before selection arose, and is equally accurate for diploid populations with incomplete dominance. For fast (e.g., seasonal) demographic changes compared to time scale for fixation of the mutant allele, and for moderate peak-to-trough ratios, we show our constant population size estimate can be used to bound the maximum and minimum population size. Applied to the Vgsc gene of Anopheles gambiae, we estimate an effective population size of roughly 6×107, and including seasonal demographic oscillations, a minimum effective population size greater than 3×107 and a maximum less than 6×109, suggesting a mean ~109.

Journal article

Hammond A, Kyrou K, Karlsson X, Galizi R, Kranjc N, Baghton A, Morianou I, Burt A, Crisanti A, Nolan Tet al., 2019, Gene drives for genetic control of the malaria mosquito, Publisher: WILEY, Pages: 62-62, ISSN: 2211-5463

Conference paper

North AR, Burt A, Godfray HCJ, 2019, Modelling the potential of genetic control of malaria mosquitoes at national scale, BMC Biology, Vol: 17, ISSN: 1741-7007

BACKGROUND: The persistence of malaria in large parts of sub-Saharan Africa has motivated the development of novel tools to complement existing control programmes, including gene-drive technologies to modify mosquito vector populations. Here, we use a stochastic simulation model to explore the potential of using a driving-Y chromosome to suppress vector populations in a 106 km2 area of West Africa including all of Burkina Faso. RESULTS: The consequence of driving-Y introductions is predicted to vary across the landscape, causing elimination of the target species in some regions and suppression in others. We explore how this variation is determined by environmental conditions, mosquito behaviour, and the properties of the gene-drive. Seasonality is particularly important, and we find population elimination is more likely in regions with mild dry seasons whereas suppression is more likely in regions with strong seasonality. CONCLUSIONS: Despite the spatial heterogeneity, we suggest that repeated introductions of modified mosquitoes over a few years into a small fraction of human settlements may be sufficient to substantially reduce the overall number of mosquitoes across the entire geographic area.

Journal article

Kyrou K, Hammond AM, Galizi R, Kranjc N, Burt A, Beaghton AK, Nolan T, Crisanti Aet al., 2018, A CRISPR-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes, Nature Biotechnology, Vol: 36, Pages: 1062-1066, ISSN: 1087-0156

In the human malaria vector Anopheles gambiae, the gene doublesex (Agdsx) encodes two alternatively spliced transcripts, dsx-female (AgdsxF) and dsx-male (AgdsxM), that control differentiation of the two sexes. The female transcript, unlike the male, contains an exon (exon 5) whose sequence is highly conserved in all Anopheles mosquitoes so far analyzed. We found that CRISPR–Cas9-targeted disruption of the intron 4–exon 5 boundary aimed at blocking the formation of functional AgdsxF did not affect male development or fertility, whereas females homozygous for the disrupted allele showed an intersex phenotype and complete sterility. A CRISPR–Cas9 gene drive construct targeting this same sequence spread rapidly in caged mosquitoes, reaching 100% prevalence within 7–11 generations while progressively reducing egg production to the point of total population collapse. Owing to functional constraint of the target sequence, no selection of alleles resistant to the gene drive occurred in these laboratory experiments. Cas9-resistant variants arose in each generation at the target site but did not block the spread of the drive.

Journal article

Burt A, Deredec A, 2018, Self-limiting population genetic control with sex-linked genome editors, Proceedings of the Royal Society B: Biological Sciences, Vol: 285, Pages: 1-9, ISSN: 0962-8452

In male heterogametic species the Y chromosome is transmitted solely from fathers to sons, and is selected for based only on its impacts on male fitness. This fact can be exploited to develop efficient pest control strategies that use Y-linked editors to disrupt the fitness of female descendants. With simple population genetic and dynamic models we show that Y-linked editors can be substantially more efficient than other self-limiting strategies and, while not as efficient as gene drive approaches, are expected to have less impact on non-target populations with which there is some gene flow. Efficiency can be further augmented by simultaneously releasing an autosomal X-shredder construct, in either the same or different males. Y-linked editors may be an attractive option to consider when efficient control of a species is desired in some locales but not others.

Journal article

Lambert B, North A, Burt A, Godfray HCJet al., 2018, The use of driving endonuclease genes to suppress mosquito vectors of malaria in temporally variable environments, MALARIA JOURNAL, Vol: 17, ISSN: 1475-2875

BackgroundThe use of gene drive systems to manipulate populations of malaria vectors is currently being investigated as a method of malaria control. One potential system uses driving endonuclease genes (DEGs) to spread genes that impose a genetic load. Previously, models have shown that the introduction of DEG-bearing mosquitoes could suppress or even extinguish vector populations in spatially-heterogeneous environments which were constant over time. In this study, a stochastic spatially-explicit model of mosquito ecology is combined with a rainfall model which enables the generation of a variety of daily precipitation patterns. The model is then used to investigate how releases of a DEG that cause a bias in population sex ratios towards males are affected by seasonal or random rainfall patterns. The parameters of the rainfall model are then fitted using data from Bamako, Mali, and Mbita, Kenya, to evaluate release strategies in similar climatic conditions.ResultsIn landscapes with abundant resources and large mosquito populations the spread of a DEG is reliable, irrespective of variability in rainfall. This study thus focuses mainly on landscapes with low density mosquito populations where the spread of a DEG may be sensitive to variation in rainfall. It is found that an introduced DEG will spread into its target population more reliably in wet conditions, yet an established DEG will have more impact in dry conditions. In strongly seasonal environments, it is thus preferable to release DEGs at the onset of a wet season to maximize their spread before the following dry season. If the variability in rainfall has a substantial random component, there is a net increase in the probability that a DEG release will lead to population extinction, due to the increased impact of a DEG which manages to establish in these conditions. For Bamako, where annual rainfall patterns are characterized by a long dry season, it is optimal to release a DEG at the start of the wet season

Journal article

Burt A, Crisanti A, 2018, Editorial: gene drive for vector control, Pathogens and Global Health, Vol: 111, Pages: 397-398, ISSN: 2047-7724

Journal article

Burt A, Crisanti A, 2018, Gene drive: evolved and synthetic, ACS Chemical Biology, Vol: 13, Pages: 343-346, ISSN: 1554-8929

Drive is a process of accelerated inheritance from one generation to the next that allows some genes to spread rapidly through populations even if they do not contribute to-or indeed even if they detract from-organismal survival and reproduction. Genetic elements that can spread by drive include gametic and zygotic killers, meiotic drivers, homing endonuclease genes, B chromosomes, and transposable elements. The fact that gene drive can lead to the spread of fitness-reducing traits (including lethality and sterility) makes it an attractive process to consider exploiting to control disease vectors and other pests. There are a number of efforts to develop synthetic gene drive systems, particularly focused on the mosquito-borne diseases that continue to plague us.

Journal article

Nikolov M, Ouedraogo A, Beaghton A, Beaghton P, Wenger E, Burt A, Welkhoff Pet al., 2018, POPULATION SEASONALITY AND RELEASE TIMING SIGNIFICANTLY AFFECT THE PROBABILITY OF ESTABLISHMENT FOR SMALL RELEASES OF GENE DRIVE MOSQUITOES, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 367-367, ISSN: 0002-9637

Conference paper

Miles A, Kwiatkowski D, Lawniczak M, Donnelly M, Abong'o B, Akiana J, Niang E, Amenga-Etego L, Ariani C, Asoala V, Ayala D, Besansky N, Bejon P, Burt A, Caputo B, Constant E, Coulibaly M, Dadzie S, Dao A, Della Torre A, de Souza D, Diabate A, Djogbenou L, Yawson A, Essandoh J, Faye O, Fontaine M, Guardiola M, Herren J, Hii J, Irving H, Kabula B, Kayondo J, Kemei B, Konate L, Lehmann T, Pendy N, Lucas E, Midega J, Nsango S, Ochomo E, Okumu F, O'Loughlin S, Paaijmans K, Paupy C, Samb B, Sangba-Kembi C, St Laurent B, Wondji C, Yaro Aet al., 2018, THE MALARIAGEN VECTOR OBSERVATORY: A NETWORK FOR THE GENOMIC SURVEILLANCE OF MALARIA VECTORS IN AFRICA AND SOUTHEAST ASIA, 67th Annual Meeting of the American-Society-of-Tropical-Medicine-and-Hygiene (ASTHM), Publisher: AMER SOC TROP MED & HYGIENE, Pages: 12-13, ISSN: 0002-9637

Conference paper

Benedict MQ, Burt A, Capurro ML, De Barro P, Handler AM, Hayes KR, Marshall JM, Tabachnick WJ, Adelman ZNet al., 2018, Recommendations for Laboratory Containment and Management of Gene Drive Systems in Arthropods, VECTOR-BORNE AND ZOONOTIC DISEASES, Vol: 18, Pages: 2-13, ISSN: 1530-3667

Journal article

Burt A, Coulibaly M, Crisanti A, Diabate A, Kayondo JKet al., 2018, Gene drive to reduce malaria transmission in sub-Saharan Africa, Journal of Responsible Innovation, Vol: 5, Pages: S66-S80, ISSN: 2329-9460

Despite impressive progress, malaria continues to impose a substantial burden of mortality and morbidity, particularly in sub-Saharan Africa, and new tools will be needed to achieve elimination. Gene drive is a natural process by which some genes are inherited at a greater-than-Mendelian rate and can spread through a population even if they cause harm to the organisms carrying them. Many different synthetic gene drive systems have been proposed to suppress the number of mosquitoes and/or reduce vector competence. As with any control measure, due attention should be paid to the possible evolution of resistance. No gene drive construct has yet been reported that is ‘field-ready’ for release, and when such constructs are developed, they should be assessed on a case-by-case basis. Gene drive approaches to vector control promise to have a number of key features that motivate their continued development, and scrutiny, by all concerned.

Journal article

Eckhoff PA, Wenger EA, Godfray HC, Burt Aet al., 2017, Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics, Proceedings of the National Academy of Sciences of the United States of America, Vol: 114, Pages: E255-E264, ISSN: 1091-6490

The renewed effort to eliminate malaria and permanently remove its tremendous burden highlights questions of what combination of tools would be sufficient in various settings and what new tools need to be developed. Gene drive mosquitoes constitute a promising set of tools, with multiple different possible approaches including population replacement with introduced genes limiting malaria transmission, driving-Y chromosomes to collapse a mosquito population, and gene drive disrupting a fertility gene and thereby achieving population suppression or collapse. Each of these approaches has had recent success and advances under laboratory conditions, raising the urgency for understanding how each could be deployed in the real world and the potential impacts of each. New analyses are needed as existing models of gene drive primarily focus on nonseasonal or nonspatial dynamics. We use a mechanistic, spatially explicit, stochastic, individual-based mathematical model to simulate each gene drive approach in a variety of sub-Saharan African settings. Each approach exhibits a broad region of gene construct parameter space with successful elimination of malaria transmission due to the targeted vector species. The introduction of realistic seasonality in vector population dynamics facilitates gene drive success compared with nonseasonal analyses. Spatial simulations illustrate constraints on release timing, frequency, and spatial density in the most challenging settings for construct success. Within its parameter space for success, each gene drive approach provides a tool for malaria elimination unlike anything presently available. Provided potential barriers to success are surmounted, each achieves high efficacy at reducing transmission potential and lower delivery requirements in logistically challenged settings.

Journal article

Miles A, Harding NJ, Botta G, Clarkson CS, Antao T, Kozak K, Schrider DR, Kern AD, Redmond S, Sharakhov I, Pearson RD, Bergey C, Fontaine MC, Donnelly MJ, Lawniczak MKN, Kwiatkowski DP, Ayala D, Besensky NJ, Burt A, Caputo B, della Torre A, Fontaine MC, Godfrey HCJ, Hahn MW, Midega J, Neafsey DE, O'Loughlin S, Pinto J, Riehle MM, Vernick KD, Weetman D, Wilding CS, White BJ, Troco AD, Diabate A, Costantini C, Rohatgi KR, Besansky NJ, Elissa N, Coulibaly B, Dinis J, Midegal J, Mbogo C, Bejon P, Mawejje HD, Stalker J, Rockett K, Drury E, Mead D, Jeffreys A, Hubbard C, Rowlands K, Isaacs AT, Jyothi D, Malangone C, Vauterin P, Jeffery B, Wright I, Hart L, Kluczyriski K, Cornelius V, MacInnisn B, Henrichs C, Giacomantonio Ret al., 2017, Genetic diversity of the African malaria vector Anopheles gambiae, Nature, Vol: 552, Pages: 96-100, ISSN: 0028-0836

The sustainability of malaria control in Africa is threatened by the rise of insecticide resistance in Anopheles mosquitoes, which transmit the disease1. To gain a deeper understanding of how mosquito populations are evolving, here we sequenced the genomes of 765 specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa, and identified over 50 million single nucleotide polymorphisms within the accessible genome. These data revealed complex population structure and patterns of gene flow, with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide-resistance genes, with several sweeps spreading over large geographical distances and between species. The design of new tools for mosquito control using gene-drive systems will need to take account of high levels of genetic diversity in natural mosquito populations.

Journal article

Godfray HCJ, North A, Burt A, 2017, How driving endonuclease genes can be used to combat pests and disease vectors, BMC Biology, Vol: 15, ISSN: 1741-7007

Driving endonuclease genes (DEGs) spread through a population by a non-Mendelian mechanism. In a heterozygote,the protein encoded by a DEG causes a double-strand break in the homologous chromosome opposite to where itsgene is inserted and when the break is repaired using the homologue as a template the DEG heterozygote is convertedto a homozygote. Some DEGs occur naturally while several classes of endonucleases can be engineered to spread in thisway, with CRISPR-Cas9 based systems being particularly flexible. There is great interest in using driving endonucleasegenes to impose a genetic load on insects that vector diseases or are economic pests to reduce their population density,or to introduce a beneficial gene such as one that might interrupt disease transmission. This paper reviews both thepopulation genetics and population dynamics of DEGs. It summarises the theory that guides the design of DEG constructsintended to perform different functions. It also reviews the studies that have explored the likelihood of resistance to DEGphenotypes arising, and how this risk may be reduced. The review is intended for a general audience and mathematicaldetails are kept to a minimum.

Journal article

Beaghton AK, Beaghton PJ, Burt A, 2017, Vector control with driving Y chromosomes: modelling the evolution of resistance, Malaria Journal, Vol: 16, ISSN: 1475-2875

BackgroundThe 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. MethodsA 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. ResultsThe 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. ConclusionsAs 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.

Journal article

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