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1.
Cell ; 166(1): 102-14, 2016 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-27293192

RESUMO

Co-option of RAG1 and RAG2 for antigen receptor gene assembly by V(D)J recombination was a crucial event in the evolution of jawed vertebrate adaptive immunity. RAG1/2 are proposed to have arisen from a transposable element, but definitive evidence for this is lacking. Here, we report the discovery of ProtoRAG, a DNA transposon family from lancelets, the most basal extant chordates. A typical ProtoRAG is flanked by 5-bp target site duplications and a pair of terminal inverted repeats (TIRs) resembling V(D)J recombination signal sequences. Between the TIRs reside tail-to-tail-oriented, intron-containing RAG1-like and RAG2-like genes. We demonstrate that ProtoRAG was recently active in the lancelet germline and that the lancelet RAG1/2-like proteins can mediate TIR-dependent transposon excision, host DNA recombination, transposition, and low-efficiency TIR rejoining using reaction mechanisms similar to those used by vertebrate RAGs. We propose that ProtoRAG represents a molecular "living fossil" of the long-sought RAG transposon.


Assuntos
Elementos de DNA Transponíveis , Evolução Molecular , Anfioxos/genética , Recombinação V(D)J , Animais , Proteínas de Ligação a DNA , Proteínas de Homeodomínio , Sequências Repetidas Terminais
2.
Proc Natl Acad Sci U S A ; 121(19): e2400903121, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38683992

RESUMO

The IL-17 pathway displays remarkably diverse functional modes between different subphyla, classes, and even orders, yet its driving factors remains elusive. Here, we demonstrate that the IL-17 pathway originated through domain shuffling between a Toll-like receptor (TLR)/IL-1R pathway and a neurotrophin-RTK (receptor-tyrosine-kinase) pathway (a Trunk-Torso pathway). Unlike other new pathways that evolve independently, the IL-17 pathway remains intertwined with its donor pathways throughout later evolution. This intertwining not only influenced the gains and losses of domains and components in the pathway but also drove the diversification of the pathway's functional modes among animal lineages. For instance, we reveal that the crustacean female sex hormone, a neurotrophin inducing sex differentiation, could interact with IL-17Rs and thus be classified as true IL-17s. Additionally, the insect prothoracicotropic hormone, a neurotrophin initiating ecdysis in Drosophila by binding to Torso, could bind to IL-17Rs in other insects. Furthermore, IL-17R and TLR/IL-1R pathways maintain crosstalk in amphioxus and zebrafish. Moreover, the loss of the Death domain in the pathway adaptor connection to IκB kinase and stress-activated protein kinase (CIKSs) dramatically reduced their abilities to activate nuclear factor-kappaB (NF-κB) and activator protein 1 (AP-1) in amphioxus and zebrafish. Reinstating this Death domain not only enhanced NF-κB/AP-1 activation but also strengthened anti-bacterial immunity in zebrafish larvae. This could explain why the mammalian IL-17 pathway, whose CIKS also lacks Death, is considered a weak signaling activator, relying on synergies with other pathways. Our findings provide insights into the functional diversity of the IL-17 pathway and unveil evolutionary principles that could govern the pathway and be used to redesign and manipulate it.


Assuntos
Interleucina-17 , Transdução de Sinais , Receptores Toll-Like , Animais , Interleucina-17/metabolismo , Receptores Toll-Like/metabolismo , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/genética , Receptores de Interleucina-1/metabolismo , Receptores de Interleucina-1/genética , Evolução Molecular , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/genética
3.
Nature ; 569(7754): 79-84, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30971819

RESUMO

Domestication of a transposon (a DNA sequence that can change its position in a genome) to give rise to the RAG1-RAG2 recombinase (RAG) and V(D)J recombination, which produces the diverse repertoire of antibodies and T cell receptors, was a pivotal event in the evolution of the adaptive immune system of jawed vertebrates. The evolutionary adaptations that transformed the ancestral RAG transposase into a RAG recombinase with appropriately regulated DNA cleavage and transposition activities are not understood. Here, beginning with cryo-electron microscopy structures of the amphioxus ProtoRAG transposase (an evolutionary relative of RAG), we identify amino acid residues and domains the acquisition or loss of which underpins the propensity of RAG for coupled cleavage, its preference for asymmetric DNA substrates and its inability to perform transposition in cells. In particular, we identify two adaptations specific to jawed-vertebrates-arginine 848 in RAG1 and an acidic region in RAG2-that together suppress RAG-mediated transposition more than 1,000-fold. Our findings reveal a two-tiered mechanism for the suppression of RAG-mediated transposition, illuminate the evolution of V(D)J recombination and provide insight into the principles that govern the molecular domestication of transposons.


Assuntos
Elementos de DNA Transponíveis/genética , Evolução Molecular , Genes RAG-1 , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/ultraestrutura , Anfioxos/enzimologia , Recombinação V(D)J , Sequência de Aminoácidos , Animais , Sequência de Bases , Microscopia Crioeletrônica , Clivagem do DNA , Proteínas de Homeodomínio/metabolismo , Modelos Moleculares , Domínios Proteicos , Relação Estrutura-Atividade
4.
Mol Biol Evol ; 40(11)2023 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-37850912

RESUMO

A series of "molecular domestication" events are thought to have converted an invertebrate RAG-like (RAGL) transposase into the RAG1-RAG2 (RAG) recombinase, a critical enzyme for adaptive immunity in jawed vertebrates. The timing and order of these events are not well understood, in part because of a dearth of information regarding the invertebrate RAGL-A transposon family. In contrast to the abundant and divergent RAGL-B transposon family, RAGL-A most closely resembles RAG and is represented by a single orphan RAG1-like (RAG1L) gene in the genome of the hemichordate Ptychodera flava (PflRAG1L-A). Here, we provide evidence for the existence of complete RAGL-A transposons in the genomes of P. flava and several echinoderms. The predicted RAG1L-A and RAG2L-A proteins encoded by these transposons intermingle sequence features of jawed vertebrate RAG and RAGL-B transposases, leading to a prediction of DNA binding, catalytic, and transposition activities that are a hybrid of RAG and RAGL-B. Similarly, the terminal inverted repeats (TIRs) of the RAGL-A transposons combine features of both RAGL-B transposon TIRs and RAG recombination signal sequences. Unlike all previously described RAG2L proteins, RAG2L-A proteins contain an acidic hinge region, which we demonstrate is capable of efficiently inhibiting RAG-mediated transposition. Our findings provide evidence for a critical intermediate in RAG evolution and argue that certain adaptations thought to be specific to jawed vertebrates (e.g. the RAG2 acidic hinge) actually arose in invertebrates, thereby focusing attention on other adaptations as the pivotal steps in the completion of RAG domestication in jawed vertebrates.


Assuntos
Elementos de DNA Transponíveis , Proteínas de Homeodomínio , Animais , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Vertebrados/genética , Vertebrados/metabolismo , Imunidade Adaptativa/genética
5.
Trends Genet ; 37(5): 414-420, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33867017

RESUMO

The relationship between human genetic variation and disease has not been fully elucidated. According to the present view on infectious diseases pathogen resistance is linked to human leukocyte antigen (HLA) class I/II variants and their individual capacity to present pathogen-derived peptides. Yet, T cell education in the thymus occurs through negative and positive selection, and both processes are controlled by a combination of HLA class I/II variants and peptides from the self. Therefore, the capacity of given HLA class I/II variants to bind pathogen-derived peptides is only one part of the selective process to generate effective immune responses. We thus propose that peptidome variation contributes to shaping T cell receptor (TCR) repertoires and hence individual immune responses, and that this variation represents inherent modulator epitopes.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade/fisiologia , Peptídeos/genética , Peptídeos/imunologia , Suscetibilidade a Doenças , Epitopos , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Peptídeos/metabolismo , Polimorfismo Genético , Receptores de Antígenos de Linfócitos T/imunologia
6.
J Med Virol ; 96(2): e29462, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38363015

RESUMO

Mutations associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) resistance to antiprotease nirmatrelvir were reported. We aimed to detect them in SARS-CoV-2 genomes and quasispecies retrieved in our institute before drug availability in January 2022 and to analyze the impact of mutations on protease (3CLpro) structure. We sought for 38 3CLpro nirmatrelvir resistance mutations in a set of 62 673 SARS-CoV-2 genomes obtained in our institute from respiratory samples collected between 2020 and 2023 and for these mutations in SARS-CoV-2 quasispecies for 90 samples collected in 2020, using Python. SARS-CoV-2 protease with major mutation E166V was generated with Swiss Pdb Viewer and Molegro Molecular Viewer. We detected 22 (58%) of the resistance-associated mutations in 417 (0.67%) of the genomes analyzed; 325 (78%) of these genomes had been obtained from samples collected in 2020-2021. APOBEC signatures were found for 12/22 mutations. We also detected among viral quasispecies from 90 samples some minority reads harboring any of 15 nirmatrelvir resistance mutations, including E166V. Also, we predicted that E166V has a very limited effect on 3CLpro structure but may prevent drug attachment. Thus, we evidenced that mutations associated with nirmatrelvir resistance pre-existed in SARS-CoV-2 before drug availability. These findings further warrant SARS-CoV-2 genomic surveillance and SARS-CoV-2 quasispecies characterization.


Assuntos
COVID-19 , Humanos , SARS-CoV-2/genética , Endopeptidases , Peptídeo Hidrolases , Lactamas , Leucina , Mutação , Nitrilas , Antivirais/farmacologia
7.
J Immunol ; 208(1): 49-53, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34872977

RESUMO

The biological relevance of genes initially categorized as "pseudogenes" is slowly emerging, notably in innate immunity. In the HLA region on chromosome 6, HLA-H is one such pseudogene; yet, it is transcribed, and its variation is associated with immune properties. Furthermore, two HLA-H alleles, H*02:07 and H*02:14, putatively encode a complete, membrane-bound HLA protein. Here we thus hypothesized that HLA-H contributes to immune homeostasis similarly to tolerogenic molecules HLA-G, -E, and -F. We tested if HLA-H*02:07 encodes a membrane-bound protein that can inhibit the cytotoxicity of effector cells. We used an HLA-null human erythroblast cell line transduced with HLA-H*02:07 cDNA to demonstrate that HLA-H*02:07 encodes a membrane-bound protein. Additionally, using a cytotoxicity assay, our results support that K562 HLA-H*02:07 inhibits human effector IL-2-activated PBMCs and human IL-2-independent NK92-MI cell line activity. Finally, through in silico genotyping of the Denisovan genome and haplotypic association with Denisovan-derived HLA-A*11, we also show that H*02:07 is of archaic origin. Hence, admixture with archaic humans brought a functional HLA-H allele into modern European and Asian populations.


Assuntos
Membrana Celular/metabolismo , Genótipo , Proteína da Hemocromatose/genética , Células Matadoras Naturais/imunologia , Pseudogenes/genética , Alelos , Povo Asiático , Citotoxicidade Imunológica , Evolução Molecular , Frequência do Gene , Antígeno HLA-A11/genética , Haplótipos , Proteína da Hemocromatose/metabolismo , Homeostase , Humanos , Tolerância Imunológica , Células K562 , Ativação Linfocitária , População Branca
8.
Nature ; 564(7734): 64-70, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30464347

RESUMO

Vertebrates have greatly elaborated the basic chordate body plan and evolved highly distinctive genomes that have been sculpted by two whole-genome duplications. Here we sequence the genome of the Mediterranean amphioxus (Branchiostoma lanceolatum) and characterize DNA methylation, chromatin accessibility, histone modifications and transcriptomes across multiple developmental stages and adult tissues to investigate the evolution of the regulation of the chordate genome. Comparisons with vertebrates identify an intermediate stage in the evolution of differentially methylated enhancers, and a high conservation of gene expression and its cis-regulatory logic between amphioxus and vertebrates that occurs maximally at an earlier mid-embryonic phylotypic period. We analyse regulatory evolution after whole-genome duplications, and find that-in vertebrates-over 80% of broadly expressed gene families with multiple paralogues derived from whole-genome duplications have members that restricted their ancestral expression, and underwent specialization rather than subfunctionalization. Counter-intuitively, paralogues that restricted their expression increased the complexity of their regulatory landscapes. These data pave the way for a better understanding of the regulatory principles that underlie key vertebrate innovations.


Assuntos
Regulação da Expressão Gênica , Genômica , Anfioxos/genética , Vertebrados/genética , Animais , Padronização Corporal/genética , Metilação de DNA , Humanos , Anfioxos/embriologia , Anotação de Sequência Molecular , Regiões Promotoras Genéticas , Transcriptoma/genética
9.
J Med Virol ; 95(10): e29146, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37800455

RESUMO

Severe acute respiratory syndrome coronavirus 2 XBB.1.5 is the first recombinant lineage to predominate at the country and global scales. Very interestingly, like the Marseille-4B subvariant (or B.1.160) and the pandemic variant B.1.1.7 (or Alpha) previously, it has its ORF8 gene inactivated by a stop codon. We aimed here to study the distribution of stop codons in ORF8 of XBB.1.5 and non-XBB.1.5 genomes. We identified that a stop codon was present at 89 (74%) ORF8 codons in ≥1 of 15 222 404 genomes available in GISAID. The mean proportion of genomes with a stop codon per codon was 0.11% (range, 0%-7.8%). In addition, a stop codon was detected at 15 (12%) codons in at least 1000 genomes. These 15 codons are notably located on seven stem-loop hairpin regions and in the signal peptide region for the case of the XBB.1.5 lineage (codon 8). Thus, it is very likely that stop codons in ORF8 gene contributed on at least three occasions and independently during the pandemic to the evolutionary success of a lineage that became transiently predominant. Such association of gene loss with evolutionary success, which suits the recently described Mistigri rule, is an important biological phenomenon very unknown in virology while largely described in cellular organisms.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Códon de Terminação , COVID-19/epidemiologia , Filogenia
10.
J Med Virol ; 95(11): e29209, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37937701

RESUMO

The tremendous majority of RNA genomes from pathogenic viruses analyzed and deposited in databases are consensus or "democratic" genomes. They represent the genomes most frequently found in the clinical samples of patients but do not account for the huge genetic diversity of coexisting genomes, which is better described as quasispecies. A viral quasispecies is defined as the dynamic distribution of nonidentical but closely related mutants, variants, recombinant, or reassortant viral genomes. Viral quasispecies have collective behavior and dynamics and are the subject of internal interactions that comprise interference, complementation, or cooperation. In the setting of SARS-CoV-2 infection, intrahost SARS-CoV-2 genetic diversity was recently notably reported for immunocompromised, chronically infected patients, for patients treated with monoclonal antibodies targeting the viral spike protein, and for different body compartments of a single patient. A question that deserves attention is whether such diversity is generated postinfection from a clonal genome in response to selection pressure or is already present at the time of infection as a quasispecies. In the present review, we summarize the data supporting that hosts are infected by a "wild bunch" of viruses rather than by multiple virions sharing the same genome. Each virion in the "wild bunch" may have different virulence and tissue tropisms. As the number of viruses replicated during host infections is huge, a viral quasispecies at any time of infection is wide and is also influenced by host-specific selection pressure after infection, which accounts for the difficulty in deciphering and predicting the appearance of more fit variants and the evolution of epidemics of novel RNA viruses.


Assuntos
COVID-19 , Vírus de RNA , Vírus , Humanos , Quase-Espécies , Vírus/genética , Vírus de RNA/genética , COVID-19/genética , Genoma Viral , Proteínas Virais/genética
11.
J Med Virol ; 95(1): e28102, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36031728

RESUMO

The nature and dynamics of mutations associated with the emergence, spread, and vanishing of SARS-CoV-2 variants causing successive waves are complex. We determined the kinetics of the most common French variant ("Marseille-4") for 10 months since its onset in July 2020. Here, we analyzed and classified into subvariants and lineages 7453 genomes obtained by next-generation sequencing. We identified two subvariants, Marseille-4A, which contains 22 different lineages of at least 50 genomes, and Marseille-4B. Their average lifetime was 4.1 ± 1.4 months, during which 4.1 ± 2.6 mutations accumulated. Growth rate was 0.079 ± 0.045, varying from 0.010 to 0.173. Most of the lineages exhibited a bell-shaped distribution. Several beneficial mutations at unpredicted sites initiated a new outbreak, while the accumulation of other mutations resulted in more viral heterogenicity, increased diversity and vanishing of the lineages. Marseille-4B emerged when the other Marseille-4 lineages vanished. Its ORF8 gene was knocked out by a stop codon, as reported in SARS-CoV-2 of mink and in the Alpha variant. This subvariant was associated with increased hospitalization and death rates, suggesting that ORF8 is a nonvirulence gene. We speculate that the observed heterogenicity of a lineage may predict the end of the outbreak.


Assuntos
COVID-19 , Epidemias , Vírus de RNA , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , Filogenia
12.
Trends Immunol ; 41(7): 561-571, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32467030

RESUMO

How innate immunity gave rise to adaptive immunity in vertebrates remains unknown. We propose an evolutionary scenario beginning with pathogen-associated molecular pattern(s) (PAMPs) being presented by molecule(s) on one cell to specific receptor(s) on other cells, much like MHC molecules and T cell receptors (TCRs). In this model, mutations in MHC-like molecule(s) that bound new PAMP(s) would not be recognized by original TCR-like molecule(s), and new MHC-like gene(s) would be lost by neutral drift. Integrating recombination activating gene (RAG) transposon(s) in a TCR-like gene would result in greater recognition diversity, with new MHC-like variants recognized and selected, along with a new RAG/TCR-like system. MHC genes would be selected to present many peptides, through multigene families, allelic polymorphism, and peptide-binding promiscuity.


Assuntos
Elementos de DNA Transponíveis , Genes RAG-1 , Complexo Principal de Histocompatibilidade , Receptores de Antígenos de Linfócitos T , Imunidade Adaptativa/genética , Animais , Elementos de DNA Transponíveis/genética , Evolução Molecular , Genes RAG-1/genética , Imunidade Inata/genética , Complexo Principal de Histocompatibilidade/genética , Receptores de Antígenos de Linfócitos T/genética
13.
Genetica ; 150(5): 247-262, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36083388

RESUMO

Correctly delimiting species and populations is a prerequisite for studies of connectivity, adaptation and conservation. Genomic data are particularly useful to test species differentiation for organisms with few informative morphological characters or low discrimination of cytoplasmic markers, as in Scleractinians. Here we applied Restriction site Associated DNA sequencing (RAD-sequencing) to the study of species differentiation and genetic structure in populations of Pocillopora spp. from Oman and French Polynesia, with the objectives to test species hypotheses, and to study the genetic structure among sampling sites within species. We focused here on coral colonies morphologically similar to P. acuta (damicornis type ß). We tested the impact of different filtering strategies on the stability of the results. The main genetic differentiation was observed between samples from Oman and French Polynesia. These samples corresponded to different previously defined primary species hypotheses (PSH), i.e., PSHs 12 and 13 in Oman, and PSH 5 in French Polynesia. In Oman, we did not observe any clear differentiation between the two putative species PSH 12 and 13, nor between sampling sites. In French Polynesia, where a single species hypothesis was studied, there was no differentiation between sites. Our analyses allowed the identification of clonal lineages in Oman and French Polynesia. The impact of clonality on genetic diversity is discussed in light of individual-based simulations.


Assuntos
Antozoários , Animais , Antozoários/genética , Estruturas Genéticas , Metagenômica , Análise de Sequência de DNA , Especificidade da Espécie
14.
Nature ; 531(7593): 249-52, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26934229

RESUMO

Since their discovery, giant viruses have revealed several unique features that challenge the conventional definition of a virus, such as their large and complex genomes, their infection by virophages and their presence of transferable short element transpovirons. Here we investigate the sensitivity of mimivirus to virophage infection in a collection of 59 viral strains and demonstrate lineage specificity in the resistance of mimivirus to Zamilon, a unique virophage that can infect lineages B and C of mimivirus but not lineage A. We hypothesized that mimiviruses harbour a defence mechanism resembling the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas system that is widely present in bacteria and archaea. We performed de novo sequencing of 45 new mimivirus strains and searched for sequences specific to Zamilon in a total of 60 mimivirus genomes. We found that lineage A strains are resistant to Zamilon and contain the insertion of a repeated Zamilon sequence within an operon, here named the 'mimivirus virophage resistance element' (MIMIVIRE). Further analyses of the surrounding sequences showed that this locus is reminiscent of a defence mechanism related to the CRISPR-Cas system. Silencing the repeated sequence and the MIMIVIRE genes restores mimivirus susceptibility to Zamilon. The MIMIVIRE proteins possess the typical functions (nuclease and helicase) involved in the degradation of foreign nucleic acids. The viral defence system, MIMIVIRE, represents a nucleic-acid-based immunity against virophage infection.


Assuntos
Mimiviridae/genética , Mimiviridae/imunologia , Vírus/imunologia , Sequência de Bases , Sistemas CRISPR-Cas/genética , Cromossomos/genética , DNA Helicases/genética , DNA Helicases/metabolismo , DNA Viral/genética , DNA Viral/metabolismo , Desoxirribonucleases/genética , Desoxirribonucleases/metabolismo , Genes Virais/genética , Genoma Viral/genética , Mimiviridae/classificação , Mimiviridae/enzimologia , Óperon/genética , Proteínas Virais/genética , Proteínas Virais/metabolismo , Vírus/genética
15.
Int J Mol Sci ; 23(5)2022 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-35269808

RESUMO

We propose a new hypothesis that explains the maintenance and evolution of MHC polymorphism. It is based on two phenomena: the constitution of the repertoire of naive T lymphocytes and the evolution of the pathogen and its impact on the immune memory of T lymphocytes. Concerning the latter, pathogen evolution will have a different impact on reinfection depending on the MHC allomorph. If a mutation occurs in a given region, in the case of MHC allotypes, which do not recognize the peptide in this region, the mutation will have no impact on the memory repertoire. In the case where the MHC allomorph binds to the ancestral peptides and not to the mutated peptide, that individual will have a higher chance of being reinfected. This difference in fitness will lead to a variation of the allele frequency in the next generation. Data from the SARS-CoV-2 pandemic already support a significant part of this hypothesis and following up on these data may enable it to be confirmed. This hypothesis could explain why some individuals after vaccination respond less well than others to variants and leads to predict the probability of reinfection after a first infection depending upon the variant and the HLA allomorph.


Assuntos
COVID-19/imunologia , Antígenos HLA/imunologia , Polimorfismo Genético/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , COVID-19/epidemiologia , COVID-19/virologia , Evolução Molecular , Frequência do Gene , Antígenos HLA/genética , Antígenos HLA/metabolismo , Humanos , Imunidade Inata/genética , Imunidade Inata/imunologia , Mutação/genética , Mutação/imunologia , Pandemias , Peptídeos/imunologia , Peptídeos/metabolismo , Polimorfismo Genético/genética , SARS-CoV-2/fisiologia , Linfócitos T/citologia , Linfócitos T/metabolismo
16.
Int J Mol Sci ; 23(11)2022 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-35682819

RESUMO

Circadian rhythms are present in almost all living organisms, and their activity relies on molecular clocks. In prokaryotes, a functional molecular clock has been defined only in cyanobacteria. Here, we investigated the presence of circadian rhythms in non-cyanobacterial prokaryotes. The bioinformatic approach was used to identify a homologue of KaiC (circadian gene in cyanobacteria) in Escherichia coli. Then, strains of E. coli (wild type and mutants) were grown on blood agar, and sampling was made every 3 h for 24 h at constant conditions. Gene expression was determined by qRT-PCR, and the rhythmicity was analyzed using the Cosinor model. We identified RadA as a KaiC homologue in E. coli. Expression of radA showed a circadian rhythm persisting at least 3 days, with a peak in the morning. The circadian expression of other E. coli genes was also observed. Gene circadian oscillations were lost in radA mutants of E. coli. This study provides evidence of molecular clock gene expression in E. coli with a circadian rhythm. Such a finding paves the way for new perspectives in antibacterial treatment.


Assuntos
Relógios Circadianos , Cianobactérias , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Relógios Circadianos/genética , Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Cianobactérias/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Fosforilação
17.
Int J Mol Sci ; 21(17)2020 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-32872436

RESUMO

The probability of the evolution of a character depends on two factors: the probability of moving from one character state to another character state and the probability of the new character state fixation. The more the evolution of a character is probable, the more the convergent evolution will be witnessed, and consequently, convergent evolution could mean that the convergent character evolution results as a combination of these two factors. We investigated this phenomenon by studying the convergent evolution of biochemical functions. For the investigation we used the case of ß-lactamases. ß-lactamases hydrolyze ß-lactams, which are antimicrobials able to block the DD-peptidases involved in bacterial cell wall synthesis. ß-lactamase activity is present in two different superfamilies: the metallo-ß-lactamase and the serine ß-lactamase. The mechanism used to hydrolyze the ß-lactam is different for the two superfamilies. We named this kind of evolution an allo-convergent evolution. We further showed that the ß-lactamase activity evolved several times within each superfamily, a convergent evolution type that we named iso-convergent evolution. Both types of convergent evolution can be explained by the two evolutionary mechanisms discussed above. The probability of moving from one state to another is explained by the promiscuous ß-lactamase activity present in the ancestral sequences of each superfamily, while the probability of fixation is explained in part by positive selection, as the organisms having ß-lactamase activity allows them to resist organisms that secrete ß-lactams. Indeed, an organism that has a mutation that increases the ß-lactamase activity will be selected, as the organisms having this activity will have an advantage over the others.


Assuntos
Bactérias/enzimologia , beta-Lactamases/química , beta-Lactamases/metabolismo , Bactérias/química , Bactérias/genética , Evolução Molecular , Hidrólise , Modelos Moleculares , Família Multigênica , Mutação , Conformação Proteica , beta-Lactamases/genética , beta-Lactamas/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-30783007

RESUMO

ß-Lactamase enzymes have attracted substential medical attention from researchers and clinicians because of their clinical, ecological, and evolutionary interest. Here, we present a comprehensive online database of ß-lactamase enzymes. The current database is manually curated and incorporates the primary amino acid sequences, closest structural information in an external structure database (the Protein Data Bank [PDB]) and the functional profiles and phylogenetic trees of the four molecular classes (A, B, C, and D) of ß-lactamases. The functional profiles are presented according to the MICs and kinetic parameters that make them more useful for the investigators. Here, a total of 1,147 ß-lactam resistance genes are analyzed and described in the database. The database is implemented in MySQL and the related website is developed with Zend Framework 2 on an Apache server, supporting all major web browsers. Users can easily retrieve and visualize biologically important information using a set of efficient queries from a graphical interface. This database is freely accessible at http://ifr48.timone.univ-mrs.fr/beta-lactamase/public/.


Assuntos
Bases de Dados de Proteínas , beta-Lactamases/metabolismo , Cinética , Testes de Sensibilidade Microbiana , Filogenia , Conformação Proteica
19.
Nature ; 500(7463): 453-7, 2013 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-23873043

RESUMO

Loss of sexual reproduction is considered an evolutionary dead end for metazoans, but bdelloid rotifers challenge this view as they appear to have persisted asexually for millions of years. Neither male sex organs nor meiosis have ever been observed in these microscopic animals: oocytes are formed through mitotic divisions, with no reduction of chromosome number and no indication of chromosome pairing. However, current evidence does not exclude that they may engage in sex on rare, cryptic occasions. Here we report the genome of a bdelloid rotifer, Adineta vaga (Davis, 1873), and show that its structure is incompatible with conventional meiosis. At gene scale, the genome of A. vaga is tetraploid and comprises both anciently duplicated segments and less divergent allelic regions. However, in contrast to sexual species, the allelic regions are rearranged and sometimes even found on the same chromosome. Such structure does not allow meiotic pairing; instead, we find abundant evidence of gene conversion, which may limit the accumulation of deleterious mutations in the absence of meiosis. Gene families involved in resistance to oxidation, carbohydrate metabolism and defence against transposons are significantly expanded, which may explain why transposable elements cover only 3% of the assembled sequence. Furthermore, 8% of the genes are likely to be of non-metazoan origin and were probably acquired horizontally. This apparent convergence between bdelloids and prokaryotes sheds new light on the evolutionary significance of sex.


Assuntos
Evolução Biológica , Conversão Gênica/genética , Genoma/genética , Reprodução Assexuada/genética , Rotíferos/genética , Animais , Transferência Genética Horizontal/genética , Genômica , Meiose/genética , Modelos Biológicos , Tetraploidia
20.
BMC Evol Biol ; 17(1): 75, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28274202

RESUMO

BACKGROUND: Horizontal transfer plays an important role in the evolution of bacterial genomes, yet it obeys several constraints, including the ecological opportunity to meet other organisms, the presence of transfer systems, and the fitness of the transferred genes. Bacteria from the Planctomyctetes, Verrumicrobia, Chlamydiae (PVC) super-phylum have a compartmentalized cell plan delimited by an intracytoplasmic membrane that might constitute an additional constraint with particular impact on bacterial evolution. In this investigation, we studied the evolution of 33 genomes from PVC species and focused on the rate and the nature of horizontally transferred sequences in relation to their habitat and their cell plan. RESULTS: Using a comparative phylogenomic approach, we showed that habitat influences the evolution of the bacterial genome's content and the flux of horizontal transfer of DNA (HT). Thus bacteria from soil, from insects and ubiquitous bacteria presented the highest average of horizontal transfer compared to bacteria living in water, extracellular bacteria in vertebrates, bacteria from amoeba and intracellular bacteria in vertebrates (with a mean of 379 versus 110 events per species, respectively and 7.6% of each genomes due to HT against 4.8%). The partners of these transfers were mainly bacterial organisms (94.9%); they allowed us to differentiate environmental bacteria, which exchanged more with Proteobacteria, and bacteria from vertebrates, which exchanged more with Firmicutes. The functional analysis of the horizontal transfers revealed a convergent evolution, with an over-representation of genes encoding for membrane biogenesis and lipid metabolism, among compartmentalized bacteria in the different habitats. CONCLUSIONS: The presence of an intracytoplasmic membrane in PVC species seems to affect the genome's evolution through the selection of transferred DNA, according to their encoded functions.


Assuntos
Bactérias/genética , Evolução Molecular , Genoma Bacteriano , Bactérias/classificação , Transferência Genética Horizontal , Filogenia
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