Accumulation Of Point Mutations Research Articles

Strategies for tularemia pathogen survival, spread and virulence

The bacterium Francisella tularensis is the etiological agent of tularemia, a natural focal, especially dangerous infection, which, “thanks to” its low infectious dose and ability to be transmitted to humans via all possible routes, is a potential bioterrorism agent. This pathogen has been known to mankind for over a hundred years, but it is still impossible to prevent massive human disease outbreaks and sporadic incidence cases, whereas tularemia diagnosis may be verified within several days-to-weeks. The basis for tularemia causative agent virulence is based on its ability to disrupt phagocyte function. In animals and humans, the various Francisella tularensis systems work together to bypass host immune system, attach to and enter eukaryotic cells, block phagosome-lysosome fusion, multiply in various host cells without being detected, inhibit their destruction and cause host cell death to release bacteria and infect neighboring tissue cells, thus developing an infectious disease in different organs. This is achieved through a unique complement-dependent penetration process into host cell, called loop phagocytosis, and an unusual inert endotoxin as well as variation in diverse forms of “free” lipid A modifications and lipid A in the LPS composition, its dynamic acyl chain length regulation, and specifically combined regulatory factors to induce the “pathogenicity island” protein synthesis. Accumulated point mutations, intragenomic rearrangements, deletions, insertions, duplications, transpositions, gene degradation, variation in the number of copies in repeated DNA sequences, as well as homologous and non-homologous recombinations underlie a markedly expanded potential for existence of the tularemia causative agent: they contribute to the holarctic subspecies strain survival in varying conditions, including osmotic shock, to form multiple resistance to various toxic substances and alter F. tularensis subspecies virulence. Analyzing a whole body of publications on the abovementioned aspects for tularemia causative agent life activity attempts to combine the differences, structural features and “tricks” of the F. tularensis species cells allowing them to be a powerful pathogen, with a high potential to adapt upon low pathogen variability and a limited genome length compared with other specially dangerous bacteria.

A functional and structural comparative analysis of large tumor antigens reveals evolution of different importin α-dependent nuclear localization signals.

Nucleocytoplasmic transport regulates the passage of proteins between the nucleus and cytoplasm. In the best characterized pathway, importin (IMP) α bridges cargoes bearing basic, classical nuclear localization signals (cNLSs) to IMPβ1, which mediates transport through the nuclear pore complex. IMPα recognizes three types of cNLSs via two binding sites: the major binding site accommodates monopartite cNLSs, the minor binding site recognizes atypical cNLSs, while bipartite cNLSs simultaneously interact with both major and minor sites. Despite the growing knowledge regarding IMPα-cNLS interactions, our understanding of the evolution of cNLSs is limited. We combined bioinformatic, biochemical, functional, and structural approaches to study this phenomenon, using polyomaviruses (PyVs) large tumor antigens (LTAs) as a model. We characterized functional cNLSs from all human (H)PyV LTAs, located between the LXCXE motif and origin binding domain. Surprisingly, the prototypical SV40 monopartite NLS is not well conserved; HPyV LTA NLSs are extremely heterogenous in terms of structural organization, IMPα isoform binding, and nuclear targeting abilities, thus influencing the nuclear accumulation properties of full-length proteins. While several LTAs possess bipartite cNLSs, merkel cell PyV contains a hybrid bipartite cNLS whose upstream stretch of basic amino acids can function as an atypical cNLS, specifically binding to the IMPα minor site upon deletion of the downstream amino acids after viral integration in the host genome. Therefore, duplication of a monopartite cNLS and subsequent accumulation of point mutations, optimizing interaction with distinct IMPα binding sites, led to the evolution of bipartite and atypical NLSs binding at the minor site.

A computational method for predicting the most likely evolutionary trajectories in the stepwise accumulation of resistance mutations.

Pathogen evolution of drug resistance often occurs in a stepwise manner via the accumulation of multiple mutations that in combination have a non-additive impact on fitness, a phenomenon known as epistasis. The evolution of resistance via the accumulation of point mutations in the DHFR genes of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) has been studied extensively and multiple studies have shown epistatic interactions between these mutations determine the accessible evolutionary trajectories to highly resistant multiple mutations. Here, we simulated these evolutionary trajectories using a model of molecular evolution, parameterised using Rosetta Flex ddG predictions, where selection acts to reduce the target-drug binding affinity. We observe strong agreement with pathways determined using experimentally measured IC50 values of pyrimethamine binding, which suggests binding affinity is strongly predictive of resistance and epistasis in binding affinity strongly influences the order of fixation of resistance mutations. We also infer pathways directly from the frequency of mutations found in isolate data, and observe remarkable agreement with the most likely pathways predicted by our mechanistic model, as well as those determined experimentally. This suggests mutation frequency data can be used to intuitively infer evolutionary pathways, provided sufficient sampling of the population.

Genomic epidemiology reveals early transmission of SARS-CoV-2 and mutational dynamics in Nanning, China

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants are a fatal pathogen resulting in substantial morbidity and mortality, and posing a great threat to human health with epidemics and pandemics. Methods: Next-generation sequencing (NGS) was performed to investigate the SARS-CoV-2 genomic characterization. Phylogenetic analysis of SARS-CoV-2 genomes was used to probe the evolutionary. Homology protein structure modelling was done to explore potential effect of the mutations. Results: The eighty genome sequences of SARS-CoV-2 obtained from the thirty-nine patients with COVID-19. A novel variant with mutation H625R concomitant with S50L in spike glycoprotein had been identified. Phylogenetic analysis revealed that SARS-CoV-2 variants belong to several distinct lineages. Homology modelling indicated that variant with mutation H625R and S50L increases flexibility of S1 subunit. Conclusions: SARS-CoV-2 genomes are constantly evolving by accumulation of point mutations. The amino acid H625R in combination with S50L may have a significant impact on the interaction between spike glycoprotein and ACE2.

Analysis of changes in the genome of Vibrio cholerae O1 El Tor genovariants during the current period of the cholera pandemic

Introduction. The genome variability of genetic variants of El Tor cholera agent has led to the emergence of strains carrying mutations in various genes associated with epidemically important pathogen properties. This situation requires an assessment of the trends in these changes in order to predict the pathogenic potential of previously unknown variants and promptly develop new tools for their diagnostics and prevention.
 The purpose of this work was to analyze the dynamic changes in pathogenicity and drug resistance genes of V. cholerae El Tor genetic variants from endemic countries and Russia.
 Materials and methods. We analyzed complete genome nucleotide sequences of 104 V. cholerae El Tor strains from the NCBI Gen Bank and European Nucleotide Archive databases, as well as those obtained by us. The nucleotide sequences were analyzed using the UGEN v. 45.1 software. The dendrogram was constructed using maximum parsimony algorithm in BioNumerics v.7.6 software package based on the multiple alignment generated using the Snippy 4.6.0 program.
 Results. Genomic sequences of 103 strain genovariants isolated on the territory of nine endemic countries of Asia and Africa, as well as in Russia in 1991-2022, have been compared. It is shown that the process of genovariant genome changing was multistage and occurred due to the continuous accumulation of point mutations in key (ctxB and tcpA) and additional (rtxA) genes of pathogenicity and core genes of antibiotic resistance (gyrA, parC and carR), as well as a deletion in SXT element. The most important was the change in the ctxB gene and the emergence of new genovariants with the ctxB7 allele, which replaced the previously prevalent strains. Analysis of altered genome regions of 83 strains from endemic regions has revealed eight genotypes, while the strains (21 isolates) imported to Russia belonged to only five of them including highly virulent strains with the ctxB7 allele and lost PolR biovar-specific feature due to carR gene mutation. The established close phylogenetic relatedness of genovariants from Russia with strains from endemic Asian countries confirms their importation from this region.
 Conclusion. The sequential occurrence and accumulation of mutations in the pathogenicity and drug resistance genes in the genome of genovariants in endemic regions have been shown, which leads to a change in their epidemically important features. The importation of new highly virulent genovariants into Russia has been established, which indicates the need for an ongoing assessment of changes in the genome of this pathogen for the timely development of adequate means of gene diagnostics and prevention.

Whole Genomic Constellation of Avian Reovirus Strains Isolated from Broilers with Arthritis in North Carolina, USA.

Avian reovirus (ARV) is an emerging pathogen which causes significant economic challenges to the chicken and turkey industry in the USA and globally, yet the molecular characterization of most ARV strains is restricted to a single particular gene, the sigma C gene. The genome of arthrogenic reovirus field isolates (R18-37308 and R18-38167), isolated from broiler chickens in North Carolina (NC), USA in 2018, was sequenced using long-read next-generation sequencing (NGS). The isolates were genotyped based on the amino acid sequence of sigma C (σC) followed by phylogenetic and amino acid analyses of the other 11 genomically encoded proteins for whole genomic constellation and genetic variation detection. The genomic length of the NC field strains was 23,494 bp, with 10 dsRNA segments ranging from 3959 bp (L1) to 1192 bp (S4), and the 5' and 3' untranslated regions (UTRs) of all the segments were found to be conserved. R18-37308 and R18-38167 were found to belong to genotype (G) VI based on the σC analysis and showed nucleotide and amino acid sequence identity ranging from 84.91-98.47% and 83.43-98.46%, respectively, with G VI strains. Phylogenetic analyses of individual genes of the NC strains did not define a single common ancestor among the available completely sequenced ARV strains. Nevertheless, most sequences supported the Chinese strain LY383 as a probable ancestor of these isolates. Moreover, amino acid analysis revealed multiple amino acid substitution events along the entirety of the genes, some of which were unique to each strain, which suggests significant divergence owing to the accumulation of point mutations. All genes from R18-37308 and R18-38167 were found to be clustered within genotypic clusters that included only ARVs of chicken origin, which negates the possibility of genetic pooling or host variation. Collectively, this study revealed sequence divergence between the NC field strains and reference ARV strains, including the currently used vaccine strains could help updating the vaccination regime through the inclusion of these highly divergent circulating indigenous field isolates.

A Clinically Selected Staphylococcus aureus clpP Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology.

Daptomycin is a last-resort antibiotic used for the treatment of infections caused by Gram-positive antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Treatment failure is commonly linked to accumulation of point mutations; however, the contribution of single mutations to resistance and the mechanisms underlying resistance remain incompletely understood. Here, we show that a single nucleotide polymorphism (SNP) selected during daptomycin therapy inactivates the highly conserved ClpP protease and is causing reduced susceptibility of MRSA to daptomycin, vancomycin, and β-lactam antibiotics as well as decreased expression of virulence factors. Super-resolution microscopy demonstrated that inactivation of ClpP reduced binding of daptomycin to the septal site and diminished membrane damage. In both the parental strain and the clpP strain, daptomycin inhibited the inward progression of septum synthesis, eventually leading to lysis and death of the parental strain while surviving clpP cells were able to continue synthesis of the peripheral cell wall in the presence of 10× MIC daptomycin, resulting in a rod-shaped morphology. To our knowledge, this is the first demonstration that synthesis of the outer cell wall continues in the presence of daptomycin. Collectively, our data provide novel insight into the mechanisms behind bacterial killing and resistance to this important antibiotic. Also, the study emphasizes that treatment with last-line antibiotics is selective for mutations that, like the SNP in clpP, favor antibiotic resistance over virulence gene expression.

Conformational Behavior of SARS-Cov-2 Spike Protein Variants: Evolutionary Jumps in Sequence Reverberate in Structural Dynamic Differences.

SARS-CoV-2 has evolved rapidly in the first 3 years of pandemic diffusion. The initial evolution of the virus appeared to proceed through big jumps in sequence changes rather than through the stepwise accumulation of point mutations on already established variants. Here, we examine whether this nonlinear mutational process reverberates in variations of the conformational dynamics of the SARS-CoV-2 Spike protein (S-protein), the first point of contact between the virus and the human host. We run extensive microsecond-scale molecular dynamics simulations of seven distinct variants of the protein in their fully glycosylated state and set out to elucidate possible links between the mutational spectrum of the S-protein and the structural dynamics of the respective variant, at global and local levels. The results reveal that mutation-dependent structural and dynamic modulations mostly consist of increased coordinated motions in variants that acquire stability and in an increased internal flexibility in variants that are less stable. Importantly, a limited number of functionally important substructures (the receptor binding domain, in particular) share the same time of movements in all variants, indicating efficient preorganization for functional regions dedicated to host interactions. Our results support a model in which the internal dynamics of the S-proteins from different strains varies in a way that reflects the observed random and non-stepwise jumps in sequence evolution, while conserving the functionally oriented traits of conformational dynamics necessary to support productive interactions with host receptors.

Life in plastic, it's fantastic! How Leishmania exploit genome instability to shape gene expression.

Leishmania are kinetoplastid pathogens that cause leishmaniasis, a debilitating and potentially life-threatening infection if untreated. Unusually, Leishmania regulate their gene expression largely post-transcriptionally due to the arrangement of their coding genes into polycistronic transcription units that may contain 100s of functionally unrelated genes. Yet, Leishmania are capable of rapid and responsive changes in gene expression to challenging environments, often instead correlating with dynamic changes in their genome composition, ranging from chromosome and gene copy number variations to the generation of extrachromosomal DNA and the accumulation of point mutations. Typically, such events indicate genome instability in other eukaryotes, coinciding with genetic abnormalities, but for Leishmania, exploiting these products of genome instability can provide selectable substrates to catalyse necessary gene expression changes by modifying gene copy number. Unorthodox DNA replication, DNA repair, replication stress factors and DNA repeats are recognised in Leishmania as contributors to this intrinsic instability, but how Leishmania regulate genome plasticity to enhance fitness whilst limiting toxic under- or over-expression of co-amplified and co-transcribed genes is unclear. Herein, we focus on fresh, and detailed insights that improve our understanding of genome plasticity in Leishmania. Furthermore, we discuss emerging models and factors that potentially circumvent regulatory issues arising from polycistronic transcription. Lastly, we highlight key gaps in our understanding of Leishmania genome plasticity and discuss future studies to define, in higher resolution, these complex regulatory interactions.

Genetic and pathogenic characteristics of two novel/recombinant avian orthoreovirus

In recent years, the emerging avian orthoreovirus (ARV) strains that led to viral arthritis have attracted much attention from the chicken industry worldwide, due to the significant economic losses suffered. In mid-2020, with the assistance of next-generation sequencing technology, we achieved success in characterizing two divergent avian orthoreovirus (ARV) variants (0543/SDYT) and isolating them from the broiler tendons characterized by arthritis. As suggested by the genome characterization of the 0543/SDYT strains, they belong separately to clusters Ⅰ and Ⅳ. As revealed by sequence comparison, phylogenetic, and recombination analysis, for μA, μB, and σNS genes, considerable genetic divergences were also observed in the two new isolates. However, in the case of λA, λB, μNS, σA, and σB genes, very clear clustering patterns were observed for SDYT and 0543 field strains, respectively. In terms of the μA, μNS, p10, p17 genes of SDYT isolate and μNS, p17, σC, σA genes of 0543 isolate, the lower similarity was observed with NCBI stored sequences, with nt highest identity values below 90 %. In addition, there is an intra-fragmental recombination event in the M1 gene of the SDYT strain. In regard, the multiple segmental recombination and accumulation of point mutations play a role in the newly-emerging ARV strains. Not only did the isolates strain exhibit strong replication ability in vivo, but they also displayed strong arthritogenicity in broilers with low neutralizing maternal antibodies, indicating that maternal antibody treatment may not effectively reduce the oral infection of avian orthoreovirus. These findings suggest that it is necessary to develop a new strategy for enhanced effectiveness in preventing and controlling ARV infection.

Noncanonical Mismatch Repair Protein NucS Modulates the Emergence of Antibiotic Resistance in Mycobacterium abscessus.

NucS/EndoMS-dependent noncanonical mismatch repair (MMR) ensures the stability of genomic DNA in mycobacteria and acts as a guardian of the genome by preventing the accumulation of point mutations. In order to address whether the inactivation of noncanonical MMR could increase the acquisition of drug resistance by mutation, a ΔnucS strain was constructed and explored in the emerging pathogen Mycobacterium abscessus. Deletion of nucS resulted in a mutator phenotype with increased acquisition of resistance to macrolides and aminoglycosides, the two main groups of antimycobacterial agents for M. abscessus treatment, and also to second-line drugs such as fluoroquinolones. Inactivation of the noncanonical MMR in M. abscessus led to increases of 10- to 22-fold in the appearance of spontaneous mutants resistant to the macrolide clarithromycin and the aminoglycosides amikacin, gentamicin, and apramycin, compared with the wild-type strain. Furthermore, emergence of fluoroquinolone (ciprofloxacin) resistance was detected in a nucS-deficient strain but not in a wild-type M. abscessus strain. Acquired drug resistance to macrolides and aminoglycosides was analyzed through sequencing of the 23S rRNA gene rrl and the 16S rRNA gene rrs from independent drug-resistant colonies of both strains. When the acquisition of clarithromycin resistance was examined, a different mutational profile was detected in the M. abscessus ΔnucS strain compared with the wild-type one. To summarize, M. abscessus requires the NucS-dependent noncanonical MMR pathway to prevent the emergence of drug-resistant isolates by mutation. To our knowledge, this is the first report that reveals the role of NucS in a human pathogen, and these findings have potential implications for the treatment of M. abscessus infections. IMPORTANCE Chronic infections caused by M. abscessus are an emerging challenge in public health, posing a substantial health and economic burden, especially in patients with cystic fibrosis. Treatment of M. abscessus infections with antibiotics is particularly challenging, as its complex drug resistance mechanisms, including constitutive resistance through DNA mutation, lead to high rates of treatment failure. To decipher the evolution of antibiotic resistance in M. abscessus, we studied NucS-dependent noncanonical MMR, a unique DNA repair pathway involved in genomic maintenance. Inactivation of NucS is linked to the increase of DNA mutations (hypermutation), which can confer drug resistance. Our analysis detected increased acquisition of mutations conferring resistance to first-line and second-line antibiotics. We believe that this study will improve the knowledge of how this pathogen could evolve into an untreatable infectious agent, and it uncovers a role for hypermutators in chronic infectious diseases under antibiotic pressure.

Monkeypox virus: The changing facets of a zoonotic pathogen.

In the last five years, the prevalence of monkeypox has been increasing both in the regions considered endemic for the disease (West and Central Africa) and worldwide. Indeed, in July 2022, the World Health Organization declared the ongoing global outbreak of monkeypox a public health emergency of international concern. The disease is caused by monkeypox virus (MPXV), a member of the Orthopoxvirus genus, which also includes variola virus (the causative agent of smallpox) and vaccinia virus (used in the smallpox eradication campaign). Here, we review aspects of MPXV genetic diversity and epidemiology, with an emphasis on its genome structure, host range, and relationship with other orthopoxviruses. We also summarize the most recent findings deriving from the sequencing of outbreak MPXV genomes, and we discuss the apparent changing of MPXV evolutionary trajectory, which is characterized by the accumulation of point mutations rather than by gene gains/losses. Whereas the availability of a vaccine, the relatively mild presentation of the disease, and its relatively low transmissibility speak in favor of an efficient control of the global outbreak, the wide host range of MPXV raises concerns about the possible establishment of novel reservoirs. We also call for the deployment of field surveys and genomic surveillance programs to identify and control the MPXV reservoirs in West and Central Africa.

RNase III-CLASH of multi-drug resistant Staphylococcus aureus reveals a regulatory mRNA 3′UTR required for intermediate vancomycin resistance

Treatment of methicillin-resistant Staphylococcus aureus infections is dependent on the efficacy of last-line antibiotics including vancomycin. Treatment failure is commonly linked to isolates with intermediate vancomycin resistance (termed VISA). These isolates have accumulated point mutations that collectively reduce vancomycin sensitivity, often by thickening the cell wall. Changes in regulatory small RNA expression have been correlated with antibiotic stress in VISA isolates however the functions of most RNA regulators is unknown. Here we capture RNA–RNA interactions associated with RNase III using CLASH. RNase III-CLASH uncovers hundreds of novel RNA–RNA interactions in vivo allowing functional characterisation of many sRNAs for the first time. Surprisingly, many mRNA–mRNA interactions are recovered and we find that an mRNA encoding a long 3′ untranslated region (UTR) (termed vigR 3′UTR) functions as a regulatory ‘hub’ within the RNA–RNA interaction network. We demonstrate that the vigR 3′UTR promotes expression of folD and the cell wall lytic transglycosylase isaA through direct mRNA–mRNA base-pairing. Deletion of the vigR 3′UTR re-sensitised VISA to glycopeptide treatment and both isaA and vigR 3′UTR deletions impact cell wall thickness. Our results demonstrate the utility of RNase III-CLASH and indicate that S. aureus uses mRNA-mRNA interactions to co-ordinate gene expression more widely than previously appreciated.

Deep phylogenetic-based clustering analysis uncovers new and shared mutations in SARS-CoV-2 variants as a result of directional and convergent evolution.

Nearly two decades after the last epidemic caused by a severe acute respiratory syndrome coronavirus (SARS-CoV), newly emerged SARS-CoV-2 quickly spread in 2020 and precipitated an ongoing global public health crisis. Both the continuous accumulation of point mutations, owed to the naturally imposed genomic plasticity of SARS-CoV-2 evolutionary processes, as well as viral spread over time, allow this RNA virus to gain new genetic identities, spawn novel variants and enhance its potential for immune evasion. Here, through an in-depth phylogenetic clustering analysis of upwards of 200,000 whole-genome sequences, we reveal the presence of previously unreported and hitherto unidentified mutations and recombination breakpoints in Variants of Concern (VOC) and Variants of Interest (VOI) from Brazil, India (Beta, Eta and Kappa) and the USA (Beta, Eta and Lambda). Additionally, we identify sites with shared mutations under directional evolution in the SARS-CoV-2 Spike-encoding protein of VOC and VOI, tracing a heretofore-undescribed correlation with viral spread in South America, India and the USA. Our evidence-based analysis provides well-supported evidence of similar pathways of evolution for such mutations in all SARS-CoV-2 variants and sub-lineages. This raises two pivotal points: (i) the co-circulation of variants and sub-lineages in close evolutionary environments, which sheds light onto their trajectories into convergent and directional evolution, and (ii) a linear perspective into the prospective vaccine efficacy against different SARS-CoV-2 strains.

Hemagglutinin Gene Variation Rate of H9N2 Avian Influenza Virus by Vaccine Intervention in China.

H9N2 subtype avian influenza virus (AIV) is widespread globally, with China being the main epidemic center. Inactivated virus vaccination was adopted as the main prevention method in China. In this study, 22 hemagglutinin (HA) sequences were obtained from all inactivated vaccine strains of H9N2 subtype AIVs in China since its introduction. A phylogenetic analysis of the vaccine sequences and HA sequences of all published H9N2 subtype AIVs was conducted to investigate the relationship between vaccine use and the virus genetic diversity of the virus. We found that during 2002–2006, when fewer vaccines were used, annual genetic differences between the HA sequences were mainly distributed between 0.025 and 0.075 and were mainly caused by point mutations. From 2009 to 2013, more vaccines were used, and the genetic distance between sequences was about 10 times greater than between 2002 and 2006, especially in 2013. In addition to the accumulation of point mutations, insertion mutations may be the main reason for the large genetic differences between sequences from 2009 to 2013. These findings suggest that the use of inactivated vaccines affected point mutations in the HA sequences and that the contribution of high-frequency replacement vaccine strains to the rate of virus evolution is greater than that of low-frequency replacement vaccine strains. The selection pressure of the vaccine antibody plays a certain role in regulating the variation of HA sequences in H9N2 subtype AIV.

Disentangle genus microdiversity within a complex microbial community by using a multi-distance long-read binning method: example of Candidatus Accumulibacter.

SummaryComplete genomes can be recovered from metagenomes by assembling and binning DNA sequences into metagenome assembled genomes (MAGs). Yet, the presence of microdiversity can hamper the assembly and binning processes, possibly yielding chimeric, highly fragmented and incomplete genomes. Here, the metagenomes of four samples of aerobic granular sludge bioreactors containing Candidatus (Ca.) Accumulibacter, a phosphate‐accumulating organism of interest for wastewater treatment, were sequenced with both PacBio and Illumina. Different strategies of genome assembly and binning were investigated, including published protocols and a binning procedure adapted to the binning of long contigs (MuLoBiSC). Multiple criteria were considered to select the best strategy for Ca. Accumulibacter, whose multiple strains in every sample represent a challenging microdiversity. In this case, the best strategy relies on long‐read only assembly and a custom binning procedure including MuLoBiSC in metaWRAP. Several high‐quality Ca. Accumulibacter MAGs, including a novel species, were obtained independently from different samples. Comparative genomic analysis showed that MAGs retrieved in different samples harbour genomic rearrangements in addition to accumulation of point mutations. The microdiversity of Ca. Accumulibacter, likely driven by mobile genetic elements, causes major difficulties in recovering MAGs, but it is also a hallmark of the panmictic lifestyle of these bacteria.

Treatment strategies for multiple myeloma based on molecular pathogenesis

It is well documented that multiple myeloma (MM) originates in a single plasma cell transformed by chromosome 14q translocations or chromosomal hyperdiploidy and evolves with the accumulation of point mutations of driver genes and/or cytogenetic abnormalities. Furthermore, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at premalignant stages and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes, including drug sensitivities. Generally, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs although could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to the microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, ∼20% of MM evolve neutrally in the context of strong oncogenic drivers, including high-risk IgH translocations, and are relatively resistant to IMiDs. Treatment strategies considering the genomic landscape and the pattern of clonal evolution may further improve the treatment outcome of MM.

Insights into the Genetic Evolution of Duck Hepatitis A Virus in Egypt.

Simple SummaryThe accumulation of point mutations and/or recombination between different serotypes drives the evolution of the duck hepatitis A viruses (DHAVs). Duck viral hepatitis, caused by DHAV, is a highly infectious disease that has been detected in Egypt since 1970. Low performance, nervous signs and sudden deaths of young ducklings were the main characteristics of the disease. The aim of this study was to identify the causative agent through viral and molecular detection for the causative virus. The causative virus was isolated in embryonated duck eggs (EDEs), with complete genome sequencing that indicate the clustering of our isolates reported in this study with Chinese duck hepatitis virus 1 that may help in new vaccine manufacturing and the development of a more sensitive diagnostic assays. Future studies to evaluate the potential protection of available commercial vaccines against the newly detected isolates will be needed.Duck hepatitis virus (DHV) is one of the commercially important diseases of ducklings worldwide. It is an acute and highly infectious disease of ducklings caused by three different serotypes (1–3) of duck hepatitis A virus (DHAV), and serotype 1 is the most common in poultry. To date, little is known about the prevalence and genetic characterisation of DHAV-1 in Egypt. In the current study, isolation and complete genomic analyses of DHAVs circulating in commercial duck farms in different Egyptian governorates were conducted. A total of eighteen samples were collected from six Egyptian governorates of 3–11 days old ducklings (Pekin and Mullard) with a history of nervous signs and high mortality rates. Five out of eighteen (5/18) samples were screened positive for the DHAV-1 based on the VP1 gene. These samples were individually used for virus isolation in embryonated duck embryos (EDE), followed by complete genome sequencing. Phylogenomic analyses showed that DHAV serotype I; genotype I were diversified into four different groups (1–4). Most of the recent circulating Egyptian DHAV strains are clustered within group 4, while isolates characterised within this study were clustered within group 1. Recombination analyses revealed that the emergence of a new recombinant virus—DHAV-1 strain Egypt-10/2019—through recombination. Likewise, the selective pressure analyses showed the existence, inside or near areas of the viral attachment or related functions, of positive scores highlighting the importance of natural selection and viral evolution mechanism at different protein domains. The findings of this study provide updated information on the epidemiological and genetic features of DHAV-1 strains and underscore the importance of DHAV surveillance as well as re-evaluation for currently used vaccines.

Cellular Darwinism: Regulatory networks, stochasticity, and selection in cancer development

There are strong parallels between the evolutionary origin of species within populations of organisms and new concepts for the origin of cancers within cell populations in the tissues of the body. The analogy is that cancers can be regarded as a new somatic species developing within the host organism. In both cases, understanding the processes involved requires a multi-scale analysis, including higher-level control of genetic and epigenetic changes. A key to developing successful therapeutic strategies will be to identify the processes that control heterogeneity in tissues. These include processes outside the currently dominant theory of evolution, i.e. the Modern Synthesis. Specifically, organisms can partially direct both genetic and epigenetic changes through the harnessing of chance. The loci and rates of mutation and of genome reorganisation are forms of targeted functional reorganisation of genomes. They are more likely to result in functional reorganisations compared to the slow accumulation of point mutations.

Discovery of a novel recombinant avian orthoreovirus in China

In mid-2020, using next-generation sequencing (NGS) technology, we identified a recombinant cluster 2 avian orthoreovirus (ARV) variant named PHC-2020−0545, isolated from tendons of 33-day-old broilers with leg swelling in China. Complete genomic sequencing and analyses demonstrated that the isolate was genetically significantly distinct from known ARV strains in M1 and M3 genes and its σC coding gene had an extremely high variability, compared with the identified ARV strains grouped into other genotyping cluster. Further analysis showed that many base substitutions were silent and non-silent substitutions are most likely to occur in the first positions of codons. Multiple segmental recombination, intra-segmental recombination and accumulation of point mutations might contribute to the emergence of this isolate. The PHC-2020−0545 strain had a strong replication ability in 1-day-old broilers, and mainly affected the movement, digestion and metabolism of broilers. In addition, the infection route of the isolate is related to its pathogenicity to broilers. Therefore, combined with its unique genetic characteristics and potential origin, we determined that the PHC-2020−0545 field strain is a novel recombinant ARV strain, which has certain reference value for the preparation and evaluation of new vaccines.