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Genetic Dominance Governs the Evolution and Spread of Mobile Genetic bioRxiv preprint doi: https://doi.org/10.1101/863472; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Genetic dominance governs the evolution and spread of mobile genetic 2 elements in bacteria 3 Jerónimo Rodríguez-Beltrán1*, Vidar Sørum2, Macarena Toll-Riera3, Carmen de la 4 Vega1, Rafael Peña-Miller4, Alvaro San Millán1*. 5 1 Department of Microbiology, Hospital Universitario Ramon y Cajal (IRYCIS) and 6 CIBER for Epidemiology and Public Health, Madrid, Spain. 7 2 Department of Pharmacy, UiT-The Arctic University of Norway, Tromsø, Norway. 8 3 Department of Evolutionary Biology and Environmental Studies, University of Zurich, 9 Switzerland. 10 4 Center for Genomic Sciences, Universidad Nacional Autonóma de México, 11 Cuernavaca, Mexico. 12 Correspondence: [email protected], [email protected] 13 14 Abstract 15 Mobile genetic elements (MGEs), such as plasmids, promote bacterial evolution 16 through horizontal gene transfer (HGT). However, the rules governing the repertoire 17 of traits encoded on MGEs remain unclear. In this study, we uncovered the central 18 role of genetic dominance shaping genetic cargo in MGEs, using antibiotic resistance 19 as a model system. MGEs are typically present in more than one copy per host 20 bacterium and, as a consequence, genetic dominance favors the fixation of dominant 21 mutations over recessive ones. Moreover, genetic dominance also determines the 22 phenotypic effects of horizontally acquired MGE-encoded genes, silencing recessive 23 alleles if the recipient bacterium already carries a wild-type copy of the gene. The 24 combination of these two effects governs the catalogue of genes encoded on MGEs, 25 dictating bacterial evolution through HGT. bioRxiv preprint doi: https://doi.org/10.1101/863472; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 26 Introduction 27 HGT between bacteria is largely mediated by specialized MGEs, such as plasmids 28 and bacteriophages, which provide an important source of genetic diversity and play 29 a fundamental role in bacterial ecology and evolution (1). The repertoire of accessory 30 genes encoded on MGEs and their ability to be phenotypically expressed in different 31 genetic backgrounds are key aspects of MGE-mediated evolution. There are several 32 factors known to impact horizontal gene transferability in bacteria, such as the level 33 of gene expression, the degree of protein connectivity, or the biochemical properties 34 of proteins (2-5), but the specific parameters that shape the repertoire of genes 35 encoded on MGEs remain largely unknown (6, 7). 36 Genetic dominance is the relationship between alleles of the same gene in which one 37 allele (dominant) masks the phenotypic contribution of a second allele (recessive). In 38 diploid or polyploid organisms, dominant alleles stem the establishment of new traits 39 encoded by recessive mutations (an effect known as Haldane’s sieve (8, 9)). Most 40 bacteria of human interest carry a single copy of their chromosome. In haploid 41 organisms like these, new alleles are able to produce a phenotype regardless of the 42 degree of genetic dominance of the underlying mutations. Therefore, the role of 43 genetic dominance in bacterial evolution has generally been overlooked. However, 44 the bacterial genome consists of more than the single chromosome; a myriad of 45 mobile genetic elements populate bacterial cells. Many MGEs, including plasmids 46 and filamentous phages, replicate independently of the bacterial chromosome and 47 are generally present at more than one copy per cell, with copy number ranging from 48 a handful to several hundred (10, 11). Extra-chromosomal MGEs thus produce an 49 island of local polyploidy in the bacterial genome (12, 13). Moreover, HGT in bacteria 50 mostly occurs between close relatives (14, 15), and genes encoded on mobile 51 elements can therefore create allelic redundancy with chromosomal genes. In light of 52 these evidences, genetic dominance should strongly affect both the emergence of bioRxiv preprint doi: https://doi.org/10.1101/863472; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 53 new mutations in MGE-encoded genes and the phenotypic effects of horizontally 54 transferred alleles. 55 Results and Discussion 56 To test whether genetic dominance determines the emergence of mutations in MGE- 57 encoded genes, we used a two-gene synthetic system that can confer tetracycline 58 resistance through dominant and recessive mutations (Figure 1). This construct 59 consists of a cI gene, encoding the bacteriophage λ CI repressor, in control of the 60 expression of a contiguous tetA gene, which encodes a tetracycline efflux pump (16). 61 This system provides tetracycline resistance when tetA transcription is derepressed. 62 Derepression can be achieved through mutations that either inactivate the cI gene or 63 disrupt the CI binding site upstream of tetA (Figure 1A). The repressor gene provides 64 a large target (714 bp), but we hypothesized that mutations inactivating cI would be 65 recessive, since in-trans copies of wild type CI would repress tetA. In contrast, the CI 66 binding site is a short target (166 bp), but mutations in this region are likely to be 67 dominant because they will lead to non-repressible, constitutive TetA production. 68 We produced two otherwise isogenic Escherichia coli MG1655 clones carrying the cI- 69 tetA system either as a single chromosomal copy (mono-copy treatment) or also 70 present on a pBAD plasmid with approximately 20 copies per cell (pCT, multi-copy 71 treatment) (Figure 1A). Fluctuation assays with both clones revealed a 4.84-fold 72 lower phenotypic tetracycline mutation rate in the multi-copy treatment clone, despite −12 73 the higher cI-tetA copy number (Likelihood ratio test statistic 55.0, P< 10 , Figure 74 1B). To determine if this effect was due to differential access to dominant or 75 recessive mutations, we first analyzed the mutations in the cI-tetA system and 76 confirmed that they were located in different regions in each treatment (Wilcoxon 77 signed-rank test, W= 313, P≈ 10-06, Figure 1C, Table S1). Next, we generated 78 homozygous and heterozygous mutant clones in order to measure the coefficient of 79 dominance (h) of a subset of mutations [h ranges from 0 (completely recessive) to 1 bioRxiv preprint doi: https://doi.org/10.1101/863472; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 80 (completely dominant), Figure S1-S2, Table S2]. As predicted, h was low or 81 intermediate in tetracycline resistance mutations recovered from the mono-copy 82 treatment and high in mutations from the multi-copy treatment (ANOVA effect of 83 treatment; F=70.02, df=1, P≈3x10-5; Figure 1D). 84 85 Figure 1. Genetic dominance and gene copy number modulate phenotypic mutation 86 rates. (A) Schematic representation of plasmid pCT, the experimental model and the 87 cI-tetA system (note the isogenic nature of the clones apart from the dosage of cI- 88 tetA). (B) Phenotypic tetracycline resistance mutation rates in the different clones. 89 Rifampicin mutation rates were determined to test the equal underlying mutation rate 90 of clones. Error bars represent 84% confidence intervals. (C) Location and type of 91 tetracycline resistance mutations in the mono-copy and multi-copy treatments are 92 indicated. In the cI-tetA system diagram, blue shading denotes the cI coding region, 93 and purple shading denotes the CI binding site plus the cI-tetA intergenic region. (D) 94 Coefficient of dominance (h) of 10 mutations described in panel C. Bars represent 95 the median of 8 biological replicates, error bars represent the interquartile range. bioRxiv preprint doi: https://doi.org/10.1101/863472; this version posted December 3, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 96 Our results indicate that interplay between genetic dominance and gene copy 97 number determines the rate at which phenotypic mutants emerge in bacteria. The 98 increased gene dosage provided by MGEs improves the chances of a beneficial 99 mutation being acquired but simultaneously masks the phenotypic contribution of the 100 newly acquired allele if it is recessive. To study the general effect of this interplay on 101 the evolution of MGE-encoded genes, we developed a computational model based 102 on the classic fluctuation assay ((17), Figure 2A and S3-S4). This model allows us to 103 simulate the acquisition and segregation of mutations located in an extra- 104 chromosomal MGE, in this case a plasmid, with a given copy number. With this 105 information, we can explore the frequency of phenotypic mutants in the bacterial 106 population at any time point; this frequency will depend on the distribution of mutated 107 and wild-type alleles in each individual cell and on the coefficient of dominance of 108 those mutations (Figure S4).
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