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Article ; Online: Evolution of homologous recombination rates across bacteria.

Torrance, Ellis L / Burton, Corey / Diop, Awa / Bobay, Louis-Marie

Proceedings of the National Academy of Sciences of the United States of America

2024 Volume 121, Issue 18, Page(s) e2316302121

Abstract: Bacteria are nonsexual organisms but are capable of exchanging DNA at diverse degrees through homologous recombination. Intriguingly, the rates of recombination vary immensely across lineages where some species have been described as purely clonal and ... ...

Abstract	Bacteria are nonsexual organisms but are capable of exchanging DNA at diverse degrees through homologous recombination. Intriguingly, the rates of recombination vary immensely across lineages where some species have been described as purely clonal and others as "quasi-sexual." However, estimating recombination rates has proven a difficult endeavor and estimates often vary substantially across studies. It is unclear whether these variations reflect natural variations across populations or are due to differences in methodologies. Consequently, the impact of recombination on bacterial evolution has not been extensively evaluated and the evolution of recombination rate-as a trait-remains to be accurately described. Here, we developed an approach based on Approximate Bayesian Computation that integrates multiple signals of recombination to estimate recombination rates. We inferred the rate of recombination of 162 bacterial species and one archaeon and tested the robustness of our approach. Our results confirm that recombination rates vary drastically across bacteria; however, we found that recombination rate-as a trait-is conserved in several lineages but evolves rapidly in others. Although some traits are thought to be associated with recombination rate (e.g., GC-content), we found no clear association between genomic or phenotypic traits and recombination rate. Overall, our results provide an overview of recombination rate, its evolution, and its impact on bacterial evolution.
MeSH term(s)	Bacteria/genetics ; Bacteria/classification ; Homologous Recombination ; Evolution, Molecular ; Bayes Theorem ; Models, Genetic ; Phylogeny ; Genome, Bacterial ; Recombination, Genetic
Language	English
Publishing date	2024-04-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2316302121
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Article ; Online: Longitudinal plasmode algorithms to evaluate statistical methods in realistic scenarios: an illustration applied to occupational epidemiology.

Souli, Youssra / Trudel, Xavier / Diop, Awa / Brisson, Chantal / Talbot, Denis

BMC medical research methodology

2023 Volume 23, Issue 1, Page(s) 242

Abstract: Introduction: Plasmode simulations are a type of simulations that use real data to determine the synthetic data-generating equations. Such simulations thus allow evaluating statistical methods under realistic conditions. As far as we know, no plasmode ... ...

Abstract	Introduction: Plasmode simulations are a type of simulations that use real data to determine the synthetic data-generating equations. Such simulations thus allow evaluating statistical methods under realistic conditions. As far as we know, no plasmode algorithm has been proposed for simulating longitudinal data. In this paper, we propose a longitudinal plasmode framework to generate realistic data with both a time-varying exposure and time-varying covariates. This work was motivated by the objective of comparing different methods for estimating the causal effect of a cumulative exposure to psychosocial stressors at work over time. Methods: We developed two longitudinal plasmode algorithms: a parametric and a nonparametric algorithms. Data from the PROspective Québec (PROQ) Study on Work and Health were used as an input to generate data with the proposed plasmode algorithms. We evaluated the performance of multiple estimators of the parameters of marginal structural models (MSMs): inverse probability of treatment weighting, g-computation and targeted maximum likelihood estimation. These estimators were also compared to standard regression approaches with either adjustment for baseline covariates only or with adjustment for both baseline and time-varying covariates. Results: Standard regression methods were susceptible to yield biased estimates with confidence intervals having coverage probability lower than their nominal level. The bias was much lower and coverage of confidence intervals was much closer to the nominal level when considering MSMs. Among MSM estimators, g-computation overall produced the best results relative to bias, root mean squared error and coverage of confidence intervals. No method produced unbiased estimates with adequate coverage for all parameters in the more realistic nonparametric plasmode simulation. Conclusion: The proposed longitudinal plasmode algorithms can be important methodological tools for evaluating and comparing analytical methods in realistic simulation scenarios. To facilitate the use of these algorithms, we provide R functions on GitHub. We also recommend using MSMs when estimating the effect of cumulative exposure to psychosocial stressors at work.
MeSH term(s)	Humans ; Models, Statistical ; Prospective Studies ; Computer Simulation ; Probability ; Algorithms ; Bias
Language	English
Publishing date	2023-10-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041362-2
ISSN	1471-2288 ; 1471-2288
ISSN (online)	1471-2288
ISSN	1471-2288
DOI	10.1186/s12874-023-02062-9
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Article ; Online: Gene flow and introgression are pervasive forces shaping the evolution of bacterial species.

Diop, Awa / Torrance, Ellis L / Stott, Caroline M / Bobay, Louis-Marie

Genome biology

2022 Volume 23, Issue 1, Page(s) 239

Abstract: Background: Although originally thought to evolve clonally, studies have revealed that most bacteria exchange DNA. However, it remains unclear to what extent gene flow shapes the evolution of bacterial genomes and maintains the cohesion of species.: ... ...

Abstract	Background: Although originally thought to evolve clonally, studies have revealed that most bacteria exchange DNA. However, it remains unclear to what extent gene flow shapes the evolution of bacterial genomes and maintains the cohesion of species. Results: Here, we analyze the patterns of gene flow within and between >2600 bacterial species. Our results show that fewer than 10% of bacterial species are truly clonal, indicating that purely asexual species are rare in nature. We further demonstrate that the taxonomic criterion of ~95% genome sequence identity routinely used to define bacterial species does not accurately represent a level of divergence that imposes an effective barrier to gene flow across bacterial species. Interruption of gene flow can occur at various sequence identities across lineages, generally from 90 to 98% genome identity. This likely explains why a ~95% genome sequence identity threshold has empirically been judged as a good approximation to define bacterial species. Our results support a universal mechanism where the availability of identical genomic DNA segments required to initiate homologous recombination is the primary determinant of gene flow and species boundaries in bacteria. We show that these barriers of gene flow remain porous since many distinct species maintain some level of gene flow, similar to introgression in sexual organisms. Conclusions: Overall, bacterial evolution and speciation are likely shaped by similar forces driving the evolution of sexual organisms. Our findings support a model where the interruption of gene flow-although not necessarily the initial cause of speciation-leads to the establishment of permanent and irreversible species borders.
MeSH term(s)	Gene Flow ; Genetic Speciation ; Genome, Bacterial ; Bacteria/genetics ; Homologous Recombination
Language	English
Publishing date	2022-11-10
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2040529-7
ISSN	1474-760X ; 1474-760X
ISSN (online)	1474-760X
ISSN	1474-760X
DOI	10.1186/s13059-022-02809-5
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Article ; Online: The change in estimate method for selecting confounders: A simulation study.

Talbot, Denis / Diop, Awa / Lavigne-Robichaud, Mathilde / Brisson, Chantal

Statistical methods in medical research

2021 Volume 30, Issue 9, Page(s) 2032–2044

Abstract: Background: The change in estimate is a popular approach for selecting confounders in epidemiology. It is recommended in epidemiologic textbooks and articles over significance test of coefficients, but concerns have been raised concerning its validity. ... ...

Abstract	Background: The change in estimate is a popular approach for selecting confounders in epidemiology. It is recommended in epidemiologic textbooks and articles over significance test of coefficients, but concerns have been raised concerning its validity. Few simulation studies have been conducted to investigate its performance. Methods: An extensive simulation study was realized to compare different implementations of the change in estimate method. The implementations were also compared when estimating the association of body mass index with diastolic blood pressure in the PROspective Québec Study on Work and Health. Results: All methods were susceptible to introduce important bias and to produce confidence intervals that included the true effect much less often than expected in at least some scenarios. Overall mixed results were obtained regarding the accuracy of estimators, as measured by the mean squared error. No implementation adequately differentiated confounders from non-confounders. In the real data analysis, none of the implementation decreased the estimated standard error. Conclusion: Based on these results, it is questionable whether change in estimate methods are beneficial in general, considering their low ability to improve the precision of estimates without introducing bias and inability to yield valid confidence intervals or to identify true confounders.
MeSH term(s)	Bias ; Computer Simulation ; Prospective Studies ; Research Design
Language	English
Publishing date	2021-08-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1136948-6
ISSN	1477-0334 ; 0962-2802
ISSN (online)	1477-0334
ISSN	0962-2802
DOI	10.1177/09622802211034219
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Article ; Online: Understanding the molecular basis of folding cooperativity through a comparative analysis of a multidomain protein and its isolated domains.

Santorelli, Daniele / Marcocci, Lucia / Pennacchietti, Valeria / Nardella, Caterina / Diop, Awa / Pietrangeli, Paola / Pagano, Livia / Toto, Angelo / Malagrinò, Francesca / Gianni, Stefano

The Journal of biological chemistry

2023 Volume 299, Issue 3, Page(s) 102983

Abstract: Although cooperativity is a well-established and general property of folding, our current understanding of this feature in multidomain folding is still relatively limited. In fact, there are contrasting results indicating that the constituent domains of ... ...

Abstract	Although cooperativity is a well-established and general property of folding, our current understanding of this feature in multidomain folding is still relatively limited. In fact, there are contrasting results indicating that the constituent domains of a multidomain protein may either fold independently on each other or exhibit interdependent supradomain phenomena. To address this issue, here we present the comparative analysis of the folding of a tandem repeat protein, comprising two contiguous PDZ domains, in comparison to that of its isolated constituent domains. By analyzing in detail the equilibrium and kinetics of folding at different experimental conditions, we demonstrate that despite each of the PDZ domains in isolation being capable of independent folding, at variance with previously characterized PDZ tandem repeats, the full-length construct folds and unfolds as a single cooperative unit. By exploiting quantitatively, the comparison of the folding of the tandem repeat to those observed for its constituent domains, as well as by characterizing a truncated variant lacking a short autoinhibitory segment, we successfully rationalize the molecular basis of the observed cooperativity and attempt to infer some general conclusions for multidomain systems.
MeSH term(s)	Kinetics ; Models, Molecular ; Protein Folding ; Proteins/chemistry ; Protein Conformation ; Protein Domains
Chemical Substances	Proteins
Language	English
Publishing date	2023-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.102983
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Article: Paradoxical evolution of rickettsial genomes

Diop, Awa / Didier Raoult / Pierre-Edouard Fournier

Ticks and tick-borne diseases. 2019 Feb., v. 10, no. 2

2019

Abstract: Rickettsia species are strictly intracellular bacteria that evolved approximately 150 million years ago from a presumably free-living common ancestor from the order Rickettsiales that followed a transition to an obligate intracellular lifestyle. ... ...

Abstract	Rickettsia species are strictly intracellular bacteria that evolved approximately 150 million years ago from a presumably free-living common ancestor from the order Rickettsiales that followed a transition to an obligate intracellular lifestyle. Rickettsiae are best known as human pathogens vectored by various arthropods causing a range of mild to severe human diseases. As part of their obligate intracellular lifestyle, rickettsial genomes have undergone a convergent evolution that includes a strong genomic reduction resulting from progressive gene degradation, genomic rearrangements as well as a paradoxical expansion of various genetic elements, notably small RNAs and short palindromic elements whose role remains unknown. This reductive evolutionary process is not unique to members of the Rickettsia genus but is common to several human pathogenic bacteria. Gene loss, gene duplication, DNA repeat duplication and horizontal gene transfer all have shaped rickettsial genome evolution. Gene loss mostly involved amino-acid, ATP, LPS and cell wall component biosynthesis and transcriptional regulators, but with a high preservation of toxin-antitoxin (TA) modules, recombination and DNA repair proteins. Surprisingly the most virulent Rickettsia species were shown to have the most drastically reduced and degraded genomes compared to closely related species of milder pathogenesis. In contrast, the less pathogenic species harbored the greatest number of mobile genetic elements. Thus, this distinct evolutionary process observed in Rickettsia species may be correlated with the differences in virulence and pathogenicity observed in these obligate intracellular bacteria. However, future investigations are needed to provide novel insights into the evolution of genome sizes and content, for that a better understanding of the balance between proliferation and elimination of genetic material in these intracellular bacteria is required.
Keywords	adenosine triphosphate ; amino acids ; ancestry ; animal pathogenic bacteria ; biosynthesis ; cell wall components ; convergent evolution ; DNA ; DNA repair ; gene deletion ; gene duplication ; genes ; genomics ; horizontal gene transfer ; human diseases ; interspersed repetitive sequences ; lifestyle ; pathogenesis ; Rickettsia ; RNA ; tick-borne diseases ; ticks ; transcription factors ; virulence
Language	English
Dates of publication	2019-02
Size	p. 462-469.
Publishing place	Elsevier GmbH
Document type	Article
ZDB-ID	2541872-5
ISSN	1877-9603 ; 1877-959X
ISSN (online)	1877-9603
ISSN	1877-959X
DOI	10.1016/j.ttbdis.2018.11.007
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Article ; Online: Characterization of the folding and binding properties of the PTB domain of FRS2 with phosphorylated and unphosphorylated ligands

Pennacchietti, Valeria / Pagano, Livia / Malagrinò, Francesca / Diop, Awa / Di Felice, Mariana / Di Matteo, Sara / Marcocci, Lucia / Pietrangeli, Paola / Toto, Angelo / Gianni, Stefano

Archives of Biochemistry and Biophysics. 2023 Sept., v. 745 p.109703-

2023

Abstract: PTB (PhosphoTyrosine Binding) domains are protein domains that exert their function by binding phosphotyrosine residues on other proteins. They are commonly found in a variety of signaling proteins and are important for mediating protein-protein ... ...

Abstract	PTB (PhosphoTyrosine Binding) domains are protein domains that exert their function by binding phosphotyrosine residues on other proteins. They are commonly found in a variety of signaling proteins and are important for mediating protein-protein interactions in numerous cellular processes. PTB domains can also exhibit binding to unphosphorylated ligands, suggesting that they have additional binding specificities beyond phosphotyrosine recognition. Structural studies have reported that the PTB domain from FRS2 possesses this peculiar feature, allowing it to interact with both phosphorylated and unphosphorylated ligands, such as TrkB and FGFR1, through different topologies and orientations. In an effort to elucidate the dynamic and functional properties of these protein-protein interactions, we provide a complete characterization of the folding mechanism of the PTB domain of FRS2 and the binding process to peptides mimicking specific regions of TrkB and FGFR1. By analyzing the equilibrium and kinetics of PTB folding, we propose a mechanism implying the presence of an intermediate along the folding pathway. Kinetic binding experiments performed at different ionic strengths highlighted the electrostatic nature of the interaction with both peptides. The specific role of single amino acids in early and late events of binding was pinpointed by site-directed mutagenesis. These results are discussed in light of previous experimental works on these protein systems.
Keywords	biophysics ; fibroblast growth factor receptor 1 ; ligands ; peptides ; site-directed mutagenesis ; Protein-protein interactions ; Stopped-flow ; TrkB ; FGFR1
Language	English
Dates of publication	2023-09
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	523-x
ISSN	1096-0384 ; 0003-9861
ISSN (online)	1096-0384
ISSN	0003-9861
DOI	10.1016/j.abb.2023.109703
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Article ; Online: The binding selectivity of the C-terminal SH3 domain of Grb2, but not its folding pathway, is dictated by its contiguous SH2 domain.

Di Felice, Mariana / Pagano, Livia / Pennacchietti, Valeria / Diop, Awa / Pietrangeli, Paola / Marcocci, Lucia / Di Matteo, Sara / Malagrinò, Francesca / Toto, Angelo / Gianni, Stefano

The Journal of biological chemistry

2024 Volume 300, Issue 4, Page(s) 107129

Abstract: The adaptor protein Grb2, or growth factor receptor-bound protein 2, possesses a pivotal role in the transmission of fundamental molecular signals in the cell. Despite lacking enzymatic activity, Grb2 functions as a dynamic assembly platform, ... ...

Abstract	The adaptor protein Grb2, or growth factor receptor-bound protein 2, possesses a pivotal role in the transmission of fundamental molecular signals in the cell. Despite lacking enzymatic activity, Grb2 functions as a dynamic assembly platform, orchestrating intracellular signals through its modular structure. This study delves into the energetic communication of Grb2 domains, focusing on the folding and binding properties of the C-SH3 domain linked to its neighboring SH2 domain. Surprisingly, while the folding and stability of C-SH3 remain robust and unaffected by SH2 presence, significant differences emerge in the binding properties when considered within the tandem context compared with isolated C-SH3. Through a double mutant cycle analysis, we highlighted a subset of residues, located at the interface with the SH2 domain and far from the binding site, finely regulating the binding of a peptide mimicking a physiological ligand of the C-SH3 domain. Our results have mechanistic implications about the mechanisms of specificity of the C-SH3 domain, indicating that the presence of the SH2 domain optimizes binding to its physiological target, and emphasizing the general importance of considering supramodular multidomain protein structures to understand the functional intricacies of protein-protein interaction domains.
MeSH term(s)	GRB2 Adaptor Protein/metabolism ; GRB2 Adaptor Protein/chemistry ; GRB2 Adaptor Protein/genetics ; src Homology Domains ; Humans ; Protein Folding ; Protein Binding ; Binding Sites
Chemical Substances	GRB2 Adaptor Protein ; GRB2 protein, human
Language	English
Publishing date	2024-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2024.107129
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Article ; Online: The Mechanism of Folding of Human Frataxin in Comparison to the Yeast Homologue - Broad Energy Barriers and the General Properties of the Transition State.

Pietrangeli, Paola / Marcocci, Lucia / Pennacchietti, Valeria / Diop, Awa / Di Felice, Mariana / Pagano, Livia / Malagrinò, Francesca / Toto, Angelo / Brunori, Maurizio / Gianni, Stefano

Journal of molecular biology

2024 Volume 436, Issue 10, Page(s) 168555

Abstract: The funneled energy landscape theory suggests that the folding pathway of homologous proteins should converge at the late stages of folding. In this respect, proteins displaying a broad energy landscape for folding are particularly instructive, allowing ... ...

Abstract	The funneled energy landscape theory suggests that the folding pathway of homologous proteins should converge at the late stages of folding. In this respect, proteins displaying a broad energy landscape for folding are particularly instructive, allowing inferring both the early, intermediate and late stages of folding. In this paper we explore the folding mechanisms of human frataxin, an essential mitochondrial protein linked to the neurodegenerative disorder Friedreich's ataxia. Building upon previous studies on the yeast homologue, the folding pathway of human frataxin is thoroughly examined, revealing a mechanism implying the presence of a broad energy barrier, reminiscent of the yeast counterpart. Through an extensive site-directed mutagenesis, we employed a Φ -value analysis to map native-like contacts in the folding transition state. The presence of a broad energy barrier facilitated the exploration of such contacts in both early and late folding events. We compared results from yeast and human frataxin providing insights into the impact of native topology on the folding mechanism and elucidating the properties of the underlying free energy landscape. The findings are discussed in the context of the funneled energy landscape theory of protein folding.
MeSH term(s)	Frataxin ; Iron-Binding Proteins/chemistry ; Iron-Binding Proteins/metabolism ; Iron-Binding Proteins/genetics ; Protein Folding ; Humans ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae/genetics ; Thermodynamics ; Models, Molecular ; Protein Conformation ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Mutagenesis, Site-Directed ; Kinetics
Chemical Substances	Frataxin ; Iron-Binding Proteins ; Saccharomyces cerevisiae Proteins
Language	English
Publishing date	2024-03-27
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2024.168555
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Article ; Online: Effect of statin use for the primary prevention of cardiovascular disease among older adults: a cautionary tale concerning target trials emulation.

Mésidor, Miceline / Sirois, Caroline / Guertin, Jason Robert / Schnitzer, Mireille E / Candas, Bernard / Blais, Claudia / Cossette, Benoit / Poirier, Paul / Brophy, James M / Lix, Lisa / Tadrous, Mina / Diop, Awa / Hamel, Denis / Talbot, Denis

Journal of clinical epidemiology

2024 Volume 168, Page(s) 111284

Abstract: Objectives: Evidence concerning the effect of statins in primary prevention of cardiovascular disease (CVD) among older adults is lacking. Using Quebec population-wide administrative data, we emulated a hypothetical randomized trial including older ... ...

Abstract	Objectives: Evidence concerning the effect of statins in primary prevention of cardiovascular disease (CVD) among older adults is lacking. Using Quebec population-wide administrative data, we emulated a hypothetical randomized trial including older adults >65 years on April 1, 2013, with no CVD history and no statin use in the previous year. Study design and setting: We included individuals who initiated statins and classified them as exposed if they were using statin at least 3 months after initiation and nonexposed otherwise. We followed them until March 31, 2018. The primary outcome was the composite endpoint of coronary events (myocardial infarction, coronary bypass, and percutaneous coronary intervention), stroke, and all-cause mortality. The intention-to-treat (ITT) effect was estimated with adjusted Cox models and per-protocol effect with inverse probability of censoring weighting. Results: A total of 65,096 individuals were included (mean age = 71.0 ± 5.5, female = 55.0%) and 93.7% were exposed. Whereas we observed a reduction in the composite outcome (ITT-hazard ratio (HR) = 0.75; 95% CI: 0.68-0.83) and mortality (ITT-HR = 0.69; 95% CI: 0.61-0.77) among exposed, coronary events increased (ITT-HR = 1.46; 95% CI: 1.09-1.94). All multibias E-values were low indicating that the results were not robust to unmeasured confounding, selection, and misclassification biases simultaneously. Conclusion: We cannot conclude on the effectiveness of statins in primary prevention of CVD among older adults. We caution that an in-depth reflection on sources of biases and careful interpretation of results are always required in observational studies.
MeSH term(s)	Aged ; Female ; Humans ; Cardiovascular Diseases/prevention & control ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Myocardial Infarction/prevention & control ; Primary Prevention/methods ; Stroke/prevention & control ; Male
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors
Language	English
Publishing date	2024-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	639306-8
ISSN	1878-5921 ; 0895-4356
ISSN (online)	1878-5921
ISSN	0895-4356
DOI	10.1016/j.jclinepi.2024.111284
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