Imperial College London

DrAliceLedda

Faculty of MedicineSchool of Public Health

Research Associate
 
 
 
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a.ledda Website

 
 
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G24Norfolk PlaceSt Mary's Campus

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Summary

 

Publications

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10 results found

Branger C, Ledda A, Billard-Pomares T, Doublet B, Barbe V, Roche D, Médigue C, Arlet G, Denamur Eet al., Specialization of small non-conjugative plasmids in Escherichia coli according to their family types., Microb Genom

We undertook a comprehensive comparative analysis of a collection of 30 small (<25 kb) non-conjugative Escherichia coli plasmids previously classified by the gene sharing approach into 10 families, as well as plasmids found in the National Center for Biotechnology Information (NCBI) nucleotide database sharing similar genomic sequences. In total, 302 mobilizable (belonging to 2 MOBrep and 5 MOBRNA families) and 106 non-transferable/relaxase-negative (belonging to three RELRNA families) plasmids were explored. The most striking feature was the specialization of the plasmid family types that was not related to their transmission mode and replication system. We observed a range of host strain specificity, from narrow E. coli host specificity to broad host range specificity, including a wide spectrum of Enterobacteriaceae. We found a wide variety of toxin/antitoxin systems and colicin operons in the plasmids, whose numbers and types varied according to the plasmid family type. The plasmids carried genes conferring resistance spanning almost all of the antibiotic classes, from those to which resistance developed early, such as sulphonamide, to those for which resistance has only developed recently, such as colistin. However, the prevalence of the resistance genes varied greatly according to the family type, ranging from 0 to 100 %. The evolutionary history of the plasmids based on the family type core genes showed variability within family nucleotide divergences in the range of E. coli chromosomal housekeeping genes, indicating long-term co-evolution between plasmids and host strains. In rare cases, a low evolutionary divergence suggested the massive spread of an epidemic plasmid. Overall, the importance of these small non-conjugative plasmids in bacterial adaptation varied greatly according to the type of family they belonged to, with each plasmid family having specific hosts and genetic traits.

Journal article

Vara C, Capilla L, Ferretti L, Ledda A, Sánchez-Guillén RA, Gabriel SI, Albert-Lizandra G, Florit-Sabater B, Bello-Rodríguez J, Ventura J, Searle JB, Mathias ML, Ruiz-Herrera Aet al., 2019, PRDM9 Diversity at Fine Geographical Scale Reveals Contrasting Evolutionary Patterns and Functional Constraints in Natural Populations of House Mice., Mol Biol Evol, Vol: 36, Pages: 1686-1700

One of the major challenges in evolutionary biology is the identification of the genetic basis of postzygotic reproductive isolation. Given its pivotal role in this process, here we explore the drivers that may account for the evolutionary dynamics of the PRDM9 gene between continental and island systems of chromosomal variation in house mice. Using a data set of nearly 400 wild-caught mice of Robertsonian systems, we identify the extent of PRDM9 diversity in natural house mouse populations, determine the phylogeography of PRDM9 at a local and global scale based on a new measure of pairwise genetic divergence, and analyze selective constraints. We find 57 newly described PRDM9 variants, this diversity being especially high on Madeira Island, a result that is contrary to the expectations of reduced variation for island populations. Our analysis suggest that the PRDM9 allelic variability observed in Madeira mice might be influenced by the presence of distinct chromosomal fusions resulting from a complex pattern of introgression or multiple colonization events onto the island. Importantly, we detect a significant reduction in the proportion of PRDM9 heterozygotes in Robertsonian mice, which showed a high degree of similarity in the amino acids responsible for protein-DNA binding. Our results suggest that despite the rapid evolution of PRDM9 and the variability detected in natural populations, functional constraints could facilitate the accumulation of allelic combinations that maintain recombination hotspot symmetry. We anticipate that our study will provide the basis for examining the role of different PRDM9 genetic backgrounds in reproductive isolation in natural populations.

Journal article

Branger C, Ledda A, Billard-Pomares T, Doublet B, Fouteau S, Barbe V, Roche D, Cruveiller S, Medigue C, Castellanos M, Decre D, Drieux-Rouze L, Clermont O, Glodt J, Tenaillon O, Cloeckaert A, Arlet G, Denamur Eet al., 2018, Extended-spectrum beta-lactamase-encoding genes are spreading on a wide range of Escherichia coli plasmids existing prior to the use of third-generation cephalosporins, MICROBIAL GENOMICS, Vol: 4, ISSN: 2057-5858

Journal article

Ledda A, Price JR, Cole K, Llewelyn MJ, Kearns AM, Crook DW, Paul J, Didelot Xet al., 2017, Re-emergence of methicillin susceptibility in a resistant lineage of Staphylococcus aureus, Journal of Antimicrobial Chemotherapy, Vol: 72, Pages: 1285-1288, ISSN: 1460-2091

ObjectivesMethicillin-resistant Staphylococcus aureus(MRSA) is a leading cause of hospital-associated infection. Acquired resistance is encoded by the mecAgeneor its homologue mecCbut little is known about the evolutionary dynamics involved in gain and loss of resistance.The objective of this study was toobtain an expanded understanding of S. aureusmethicilinresistance microevolution in vivo, by focusing on a single lineage.MethodsWe compared thewhole genome sequences of 231 isolates from a single epidemiclineage (clonal complex CC30 and spa-type t018)of S. aureusthat caused an epidemic in the United Kingdom. ResultsWe show that resistance to methicillin in this single lineage was gained on at least two separate occasions, one of which led to a clonal expansion around 1995 presumably caused by a selective advantage.Resistance was however subsequently lost in vivoby ninestrains isolated between 2008and 2012.We describe the genetic mechanisms involved in this loss of 40resistance and the imperfect relationship between genotypic and phenotypic resistance.ConclusionsThe recentre-emergence of methicillin susceptibility in this epidemic lineage suggests asignificant fitness cost ofresistanceand reducedselective advantage following the introduction in the mid 2000s of MRSA hospital control measures throughout the United Kingdom.

Journal article

Ledda A, Ferretti L, 2014, A simple model for the distribution of plasmid lengths

Plasmids are major players in Horizontal Gene Transfer mechanisms, hence theyare highly variable in their gene content and length. We propose a model forthe fitness of a plasmid as a function of its length, which predictsdiminishing returns. We infer the distribution of plasmid lengths by a simpleevolutionary model and we show that there is a positive correlation between thepresence and efficiency of the conjugation machinery and the length of theplasmid. The model predicts an "insertion load" on plasmids, which couldexplain also the fact that plasmids are widespread in bacterial populations butrarely established. Finally we discuss how the typical length of plasmidsincreases with the amount of stress in the environment, focusing on the recenthuman-driven increase in antibiotic concentrations.

Journal article

Lescat M, Reibel F, Pintard C, Dion S, Glodt J, Gateau C, Launay A, Ledda A, Cruveiller S, Tourret J, Tenaillon Oet al., 2014, The Conserved nhaAR Operon Is Drastically Divergent between B2 and Non-B2 Escherichia coli and Is Involved in Extra-Intestinal Virulence, PLOS One, Vol: 9, ISSN: 1932-6203

The Escherichia coli species is divided in phylogenetic groups that differ in their virulence and commensal distribution. Strains belonging to the B2 group are involved in extra-intestinal pathologies but also appear to be more prevalent as commensals among human occidental populations. To investigate the genetic specificities of B2 sub-group, we used 128 sequenced genomes and identified genes of the core genome that showed marked difference between B2 and non-B2 genomes. We focused on the gene and its surrounding region with the strongest divergence between B2 and non-B2, the antiporter gene nhaA. This gene is part of the nhaAR operon, which is in the core genome but flanked by mobile regions, and is involved in growth at high pH and high sodium concentrations. Consistently, we found that a panel of non-B2 strains grew faster than B2 at high pH and high sodium concentrations. However, we could not identify differences in expression of the nhaAR operon using fluorescence reporter plasmids. Furthermore, the operon deletion had no differential impact between B2 and non-B2 strains, and did not result in a fitness modification in a murine model of gut colonization. Nevertheless, sequence analysis and experiments in a murine model of septicemia revealed that recombination in nhaA among B2 strains was observed in strains with low virulence. Finally, nhaA and nhaAR operon deletions drastically decreased virulence in one B2 strain. This effect of nhaAR deletion appeared to be stronger than deletion of all pathogenicity islands. Thus, a population genetic approach allowed us to identify an operon in the core genome without strong effect in commensalism but with an important role in extra-intestinal virulence, a landmark of the B2 strains.

Journal article

Povolotskaya IS, Kondrashov FA, Ledda A, Vlasov PKet al., 2012, Stop codons in bacteria are not selectively equivalent, Biology Direct, Vol: 7, ISSN: 1745-6150

BACKGROUND: The evolution and genomic stop codon frequencies have not been rigorously studied with the exception of coding of non-canonical amino acids. Here we study the rate of evolution and frequency distribution of stop codons in bacterial genomes. RESULTS: We show that in bacteria stop codons evolve slower than synonymous sites, suggesting the action of weak negative selection. However, the frequency of stop codons relative to genomic nucleotide content indicated that this selection regime is not straightforward. The frequency of TAA and TGA stop codons is GC-content dependent, with TAA decreasing and TGA increasing with GC-content, while TAG frequency is independent of GC-content. Applying a formal, analytical model to these data we found that the relationship between stop codon frequencies and nucleotide content cannot be explained by mutational biases or selection on nucleotide content. However, with weak nucleotide content-dependent selection on TAG, -0.5 < Nes < 1.5, the model fits all of the data and recapitulates the relationship between TAG and nucleotide content. For biologically plausible rates of mutations we show that, in bacteria, TAG stop codon is universally associated with lower fitness, with TAA being the optimal for G-content < 16% while for G-content > 16% TGA has a higher fitness than TAG. CONCLUSIONS: Our data indicate that TAG codon is universally suboptimal in the bacterial lineage, such that TAA is likely to be the preferred stop codon for low GC content while the TGA is the preferred stop codon for high GC content. The optimization of stop codon usage may therefore be useful in genome engineering or gene expression optimization applications.

Journal article

Pirino D, Rigosa J, Ledda A, Ferretti Let al., 2012, Detecting correlations among functional-sequence motifs, Physical Review E, Vol: 85, ISSN: 1539-3755

Sequence motifs are words of nucleotides in DNA with biological functions, e.g., gene regulation. Identification of such words proceeds through rejection of Markov models on the expected motif frequency along the genome. Additional biological information can be extracted from the correlation structure among patterns of motif occurrences. In this paper a log-linear multivariate intensity Poisson model is estimated via expectation maximization on a set of motifs along the genome of E. coli K12. The proposed approach allows for excitatory as well as inhibitory interactions among motifs and between motifs and other genomic features like gene occurrences. Our findings confirm previous stylized facts about such types of interactions and shed new light on genome-maintenance functions of some particular motifs. We expect these methods to be applicable to a wider set of genomic features.

Journal article

Mularoni L, Ledda A, Toll-Riera M, Mar Alba Met al., 2010, Natural selection drives the accumulation of amino acid tandem repeats in human proteins, GENOME RESEARCH, Vol: 20, Pages: 745-754, ISSN: 1088-9051

Journal article

Salichs E, Ledda A, Mularoni L, Alba MM, de la Luna Set al., 2009, Genome-wide analysis of histidine repeats reveals their role in the localization of human proteins to the nuclear speckles compartment, PLoS Genetics, Vol: 5, Pages: 1-18, ISSN: 1553-7390

Single amino acid repeats are prevalent in eukaryote organisms, although the role of many such sequences is still poorly understood. We have performed a comprehensive analysis of the proteins containing homopolymeric histidine tracts in the human genome and identified 86 human proteins that contain stretches of five or more histidines. Most of them are endowed with DNA- and RNA-related functions, and, in addition, there is an overrepresentation of proteins expressed in the brain and/or nervous system development. An analysis of their subcellular localization shows that 15 of the 22 nuclear proteins identified accumulate in the nuclear subcompartment known as nuclear speckles. This localization is lost when the histidine repeat is deleted, and significantly, closely related paralogous proteins without histidine repeats also fail to localize to nuclear speckles. Hence, the histidine tract appears to be directly involved in targeting proteins to this compartment. The removal of DNA-binding domains or treatment with RNA polymerase II inhibitors induces the re-localization of several polyhistidine-containing proteins from the nucleoplasm to nuclear speckles. These findings highlight the dynamic relationship between sites of transcription and nuclear speckles. Therefore, we define the histidine repeats as a novel targeting signal for nuclear speckles, and we suggest that these repeats are a way of generating evolutionary diversification in gene duplicates. These data contribute to our better understanding of the physiological role of single amino acid repeats in proteins.

Journal article

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