Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jul 7;117(27):15755-15762.
doi: 10.1073/pnas.2001240117. Epub 2020 Jun 22.

Genetic dominance governs the evolution and spread of mobile genetic elements in bacteria

Jerónimo Rodríguez-Beltrán  1   2 , Vidar Sørum  2 , Macarena Toll-Riera  3 , Carmen de la Vega  4 , Rafael Peña-Miller  5 , Álvaro San Millán  1   2
Affiliations

Genetic dominance governs the evolution and spread of mobile genetic elements in bacteria

Jerónimo Rodríguez-Beltrán et al. Proc Natl Acad Sci U S A. .

Abstract

Mobile genetic elements (MGEs), such as plasmids, promote bacterial evolution through horizontal gene transfer (HGT). However, the rules governing the repertoire of traits encoded on MGEs remain unclear. In this study, we uncovered the central role of genetic dominance shaping genetic cargo in MGEs, using antibiotic resistance as a model system. MGEs are typically present in more than one copy per host bacterium, and as a consequence, genetic dominance favors the fixation of dominant mutations over recessive ones. In addition, genetic dominance also determines the phenotypic effects of horizontally acquired MGE-encoded genes, silencing recessive alleles if the recipient bacterium already carries a wild-type copy of the gene. The combination of these two effects governs the catalog of genes encoded on MGEs. Our results help to understand how MGEs evolve and spread, uncovering the neglected influence of genetic dominance on bacterial evolution. Moreover, our findings offer a framework to forecast the spread and evolvability of MGE-encoded genes, which encode traits of key human interest, such as virulence or antibiotic resistance.

Keywords: antibiotic resistance; evolution; genetic dominance; mobile genetic elements.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interest.

Figures

Fig. 1.
Fig. 1.
Genetic dominance and gene copy number modulate phenotypic mutation rates. (A) The cI-tetA system. Under normal circumstances, transcription from the lambda promoter pM drives the production of the phage repressor CI (red protein) which binds the operator boxes (O1 and O2) located upstream the tetA gene, thus blocking its expression. (B) Schematic representation of plasmids pBAD, pCT, and the experimental model (note the isogenic nature of the clones apart from the dosage of cI-tetA). (C) Tetracycline and rifampicin resistance phenotypic mutation rates in the different clones. Error bars represent 84% confidence intervals. The asterisk denotes statistical significance; n.s., nonsignificant. (D) Location and type of tetracycline resistance mutations in the monocopy (upper part) and multicopy (lower part) treatments. Blue shading denotes the cI coding region, and red shading denotes the CI binding site plus the cI-tetA intergenic region. (E) Tetracycline resistance level of the different clones constructed to measure the coefficient of dominance of tetracycline resistance mutations detailed in D. The tetracycline inhibitory concentration 90 (IC90, in mg/L) of the homozygous mutant clones (Mut) and heterozygous mutant clones (HT) are represented by boxes. The line inside the box marks the median. The upper and lower hinges correspond to the 25th and 75th percentiles, and whiskers extend to 1.5 times the interquartile range. Resistance level of the homozygous wild-type clone is indicated by a horizontal gray line for reference. The letters in the panels correspond to the mutations indicated in D. (F) Coefficient of dominance (h) of 10 mutations described in C and D. Bars represent the median of eight biological replicates; error bars represent the interquartile range.
Fig. 2.
Fig. 2.
Interplay between genetic dominance and gene copy number. (A) Results of simulations analyzing the effect of plasmid copy number and genetic dominance of a mutation on the emergence of phenotypic mutants. The chart shows fold changes in phenotypic mutation rate for a plasmid-carried gene at different copy numbers compared with a chromosomal copy of the same gene (black line). (Inset) The comparison of experimental results obtained for gyrA and folA (presented in B and C) with the prediction for a plasmid of 20 copies. (B) Fold change of antibiotic resistance phenotypic mutation rates in E. coli, comparing multicopy and monocopy treatments for gyrA, rpsL, and folA. Error bars indicate 84% confidence intervals. Note that result for rpsL is an upper bound due to the absence of phenotypic mutants in the multicopy treatment (Materials and Methods). (C) Antibiotic resistance phenotypes of the clones constructed to measure the coefficient of dominance of gyrAD87N (nalidixic acid), rpsLK43T (streptomycin), and folAL28R (trimethoprim) resistance mutations. The inhibitory concentration 90 (IC90, in mg/L) of the homozygous mutant clones (Mut), heterozygous mutant clones (HT), and homozygous wild-type clones (WT) are represented by boxes. The line inside the box marks the median. The upper and lower hinges correspond to the 25th and 75th percentiles, and whiskers extend to 1.5 times the interquartile range. Asterisks denote statistically significant differences (Student’s t test P < 0.0002 in all cases); n.s., nonsignificant. (D) Coefficient of dominance of gyrAD87N, rpsLK43T, and folAL28R. Bars represent the median of eight biological replicates; error bars represent the interquartile range.
Fig. 3.
Fig. 3.
Genetic dominance limits the phenotypic contribution of horizontally transferred recessive alleles. (A) Pictures of a representative replicate of the conjugation assays. Overnight cultures of spots inoculated from 10-fold dilutions of conjugation mixes (100 to 10−4, from left to right) on plates selecting for transconjugants. Selection on carbenicillin reveals the actual number of transconjugants; selection on carbenicillin plus nalidixic acid or trimethoprim reveals the number of transconjugants carrying gyrA and folA alleles and expressing the resistant phenotype. (B) Antibiotic resistance level conferred by a plasmid-encoded resistance allele in the recipient bacterium (when a wild-type copy of the gene is present in the chromosome), assuming phenotypic resistance as the product of plasmid copy number and the coefficient of dominance of the allele. Experimental data are presented for gyrAD87N and folAL28R in plasmid pSEVA121.
Fig. 4.
Fig. 4.
Genetic dominance shapes the bacterial mobilome. (A) Prevalence of antibiotic resistance-conferring alleles of rpoB, rpsL, gyrA, folA, and folP (indicated with an asterisk) in chromosomes and MGEs across bacteria. (B) Proportion of antibiotic resistance genes belonging to each resistance category on MGE (n = 6,053) and chromosomes (n = 26,147; see also SI Appendix, Fig. S8).
See this image and copyright information in PMC

References

    1. Wiedenbeck J., Cohan F. M., Origins of bacterial diversity through horizontal genetic transfer and adaptation to new ecological niches. FEMS Microbiol. Rev. 35, 957–976 (2011). - PubMed
    1. Sorek R.et al., Genome-wide experimental determination of barriers to horizontal gene transfer. Science 318, 1449–1452 (2007). - PubMed
    1. Jain R., Rivera M. C., Lake J. A., Horizontal gene transfer among genomes: The complexity hypothesis. Proc. Natl. Acad. Sci. U.S.A. 96, 3801–3806 (1999). - PMC - PubMed
    1. Cohen O., Gophna U., Pupko T., The complexity hypothesis revisited: Connectivity rather than function constitutes a barrier to horizontal gene transfer. Mol. Biol. Evol. 28, 1481–1489 (2011). - PubMed
    1. Porse A., Schou T. S., Munck C., Ellabaan M. M. H., Sommer M. O. A., Biochemical mechanisms determine the functional compatibility of heterologous genes. Nat. Commun. 9, 522 (2018). - PMC - PubMed

Publication types

MeSH terms

LinkOut - more resources