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  1. Article ; Online: Dinucleotide biases in the genomes of prokaryotic and eukaryotic dsDNA viruses and their hosts.

    Forni, Diego / Pozzoli, Uberto / Cagliani, Rachele / Sironi, Manuela

    Molecular ecology

    2024  Volume 33, Issue 6, Page(s) e17287

    Abstract: The genomes of cellular organisms display CpG and TpA dinucleotide composition biases. Such biases have been poorly investigated in dsDNA viruses. Here, we show that in dsDNA virus, bacterial, and eukaryotic genomes, the representation of TpA and CpG ... ...

    Abstract The genomes of cellular organisms display CpG and TpA dinucleotide composition biases. Such biases have been poorly investigated in dsDNA viruses. Here, we show that in dsDNA virus, bacterial, and eukaryotic genomes, the representation of TpA and CpG dinucleotides is strongly dependent on genomic G + C content. Thus, the classical observed/expected ratios do not fully capture dinucleotide biases across genomes. Because a larger portion of the variance in TpA frequency was explained by G + C content, we explored which additional factors drive the distribution of CpG dinucleotides. Using the residuals of the linear regressions as a measure of dinucleotide abundance and ancestral state reconstruction across eukaryotic and prokaryotic virus trees, we identified an important role for phylogeny in driving CpG representation. Nonetheless, phylogenetic ANOVA analyses showed that few host associations also account for significant variations. Among eukaryotic viruses, most significant differences were observed between arthropod-infecting viruses and viruses that infect vertebrates or unicellular organisms. However, an effect of viral DNA methylation status (either driven by the host or by viral-encoded methyltransferases) is also likely. Among prokaryotic viruses, cyanobacteria-infecting phages resulted to be significantly CpG-depleted, whereas phages that infect bacteria in the genera Burkolderia and Staphylococcus were CpG-rich. Comparison with bacterial genomes indicated that this effect is largely driven by the general tendency for phages to resemble the host's genomic CpG content. Notably, such tendency is stronger for temperate than for lytic phages. Our data shed light into the processes that shape virus genome composition and inform manipulation strategies for biotechnological applications.
    MeSH term(s) Animals ; Bias ; DNA Methylation/genetics ; Genome, Viral/genetics ; Phylogeny ; Viruses/genetics ; Prokaryotic Cells/chemistry ; Eukaryotic Cells/chemistry
    Language English
    Publishing date 2024-01-23
    Publishing country England
    Document type Journal Article
    ZDB-ID 1126687-9
    ISSN 1365-294X ; 0962-1083
    ISSN (online) 1365-294X
    ISSN 0962-1083
    DOI 10.1111/mec.17287
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: An APOBEC3 Mutational Signature in the Genomes of Human-Infecting Orthopoxviruses.

    Forni, Diego / Cagliani, Rachele / Pozzoli, Uberto / Sironi, Manuela

    mSphere

    2023  Volume 8, Issue 2, Page(s) e0006223

    Abstract: The ongoing worldwide monkeypox outbreak is caused by viral lineages (globally referred to as hMPXV1) that are related to but distinct from clade IIb MPXV viruses transmitted within Nigeria. Analysis of the genetic differences has indicated that APOBEC- ... ...

    Abstract The ongoing worldwide monkeypox outbreak is caused by viral lineages (globally referred to as hMPXV1) that are related to but distinct from clade IIb MPXV viruses transmitted within Nigeria. Analysis of the genetic differences has indicated that APOBEC-mediated editing might be responsible for the unexpectedly high number of mutations observed in hMPXV1 genomes. Here, using 1,624 publicly available hMPXV1 sequences, we analyzed the mutations that accrued between 2017 and the emergence of the current predominant variant (B.1), as well as those that that have been accumulating during the 2022 outbreak. We confirmed an overwhelming prevalence of C-to-T and G-to-A mutations, with a sequence context (5'-TC-3') consistent with the preferences of several human APOBEC3 enzymes. We also found that mutations preferentially occur in highly expressed viral genes, although no transcriptional asymmetry was observed. A comparison of the mutation spectrum and context was also performed against the human-specific variola virus (VARV) and the zoonotic cowpox virus (CPXV), as well as fowlpox virus (FWPV). The results indicated that in VARV genomes, C-to-T and G-to-A changes were more common than the opposite substitutions, although the effect was less marked than for hMPXV1. Conversely, no preference toward C-to-T and G-to-A changes was observed in CPXV and FWPV. Consistently, the sequence context of C-to-T changes confirmed a preference for a T in the -1 position for VARV, but not for CPXV or FWPV. Overall, our results strongly support the view that, irrespective of the transmission route, orthopoxviruses infecting humans are edited by the host APOBEC3 enzymes.
    MeSH term(s) Animals ; Humans ; Orthopoxvirus/genetics ; Mpox (monkeypox) ; Cowpox virus/genetics ; Cowpox virus/metabolism ; Variola virus ; Smallpox ; Mutation ; APOBEC Deaminases/genetics ; APOBEC Deaminases/metabolism
    Chemical Substances APOBEC3 proteins, human (EC 3.5.4.5) ; APOBEC Deaminases (EC 3.5.4.5)
    Language English
    Publishing date 2023-03-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2379-5042
    ISSN (online) 2379-5042
    DOI 10.1128/msphere.00062-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Analysis of variola virus molecular evolution suggests an old origin of the virus consistent with historical records.

    Forni, Diego / Molteni, Cristian / Cagliani, Rachele / Clerici, Mario / Sironi, Manuela

    Microbial genomics

    2023  Volume 9, Issue 1

    Abstract: Archaeovirology efforts provided a rich portrait of the evolutionary history of variola virus (VARV, the cause of smallpox), which was characterized by lineage extinctions and a relatively recent origin of the virus as a human pathogen (~1700 years ago, ... ...

    Abstract Archaeovirology efforts provided a rich portrait of the evolutionary history of variola virus (VARV, the cause of smallpox), which was characterized by lineage extinctions and a relatively recent origin of the virus as a human pathogen (~1700 years ago, ya). This contrasts with historical records suggesting the presence of smallpox as early as 3500 ya. By performing an analysis of ancestry components in modern, historic, and ancient genomes, we unveil the progressive drifting of VARV lineages from a common ancestral population and we show that a small proportion of Viking Age ancestry persisted until the 18th century. After the split of the P-I and P-II lineages, the former experienced a severe bottleneck. With respect to the emergence of VARV as a human pathogen, we revise time estimates by accounting for the time-dependent rate phenomenon. We thus estimate that VARV emerged earlier than 3800 ya, supporting its presence in ancient societies, as pockmarked Egyptian mummies suggest.
    MeSH term(s) Humans ; Variola virus/genetics ; Smallpox/epidemiology ; Smallpox/history ; Phylogeny ; Genome, Viral/genetics ; Evolution, Molecular
    Language English
    Publishing date 2023-02-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2835258-0
    ISSN 2057-5858 ; 2057-5858
    ISSN (online) 2057-5858
    ISSN 2057-5858
    DOI 10.1099/mgen.0.000932
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Dinucleotide biases in RNA viruses that infect vertebrates or invertebrates.

    Forni, Diego / Pozzoli, Uberto / Cagliani, Rachele / Clerici, Mario / Sironi, Manuela

    Microbiology spectrum

    2023  Volume 11, Issue 6, Page(s) e0252923

    Abstract: Importance: Akin to a molecular signature, dinucleotide composition can be exploited by the zinc-finger antiviral protein (ZAP) to restrict CpG-rich (and UpA-rich) RNA viruses. ZAP evolved in tetrapods, and it is not encoded by invertebrates and fish. ... ...

    Abstract Importance: Akin to a molecular signature, dinucleotide composition can be exploited by the zinc-finger antiviral protein (ZAP) to restrict CpG-rich (and UpA-rich) RNA viruses. ZAP evolved in tetrapods, and it is not encoded by invertebrates and fish. Because a systematic analysis is missing, we analyzed the genomes of RNA viruses that infect vertebrates or invertebrates. We show that vertebrate single-stranded (ss) RNA(+) viruses and, to a lesser extent, double-stranded RNA viruses tend to have stronger CpG bias than invertebrate viruses. Conversely, ssRNA(-) viruses have similar dinucleotide composition whether they infect vertebrates or invertebrates. Analysis of ssRNA(+) viruses that infect mammals, reptiles, and fish indicated that ZAP is unlikely to be a major driver of CpG depletion. We also show that, compared to other coronaviruses, the genome of SARS-CoV-2 is not homogeneously CpG-depleted. Our study provides new insights into virus evolution and strategies for recoding RNA virus genomes.
    MeSH term(s) Animals ; RNA Viruses/genetics ; Invertebrates/genetics ; Vertebrates/genetics ; SARS-CoV-2/genetics ; RNA ; Mammals
    Chemical Substances RNA (63231-63-0)
    Language English
    Publishing date 2023-10-06
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2807133-5
    ISSN 2165-0497 ; 2165-0497
    ISSN (online) 2165-0497
    ISSN 2165-0497
    DOI 10.1128/spectrum.02529-23
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Disease-causing human viruses: novelty and legacy.

    Forni, Diego / Cagliani, Rachele / Clerici, Mario / Sironi, Manuela

    Trends in microbiology

    2022  Volume 30, Issue 12, Page(s) 1232–1242

    Abstract: About 270 viruses are known to infect humans. Some of these viruses have been known for centuries, whereas others have recently emerged. During their evolutionary history, humans have moved out of Africa to populate the world. In historical times, human ... ...

    Abstract About 270 viruses are known to infect humans. Some of these viruses have been known for centuries, whereas others have recently emerged. During their evolutionary history, humans have moved out of Africa to populate the world. In historical times, human migrations resulted in the displacement of large numbers of people. All these events determined the movement and dispersal of human-infecting viruses. Technological advances have resulted in the characterization of the genetic variability of human viruses, both in extant and in archaeological samples. Field studies investigated the diversity of viruses hosted by other animals. In turn, these advances provided insight into the evolutionary history of human viruses back in time and defined the key events through which they originated and spread.
    MeSH term(s) Animals ; Humans ; Biological Evolution ; Viruses/genetics ; Africa ; Phylogeny
    Language English
    Publishing date 2022-07-25
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1158963-2
    ISSN 1878-4380 ; 0966-842X
    ISSN (online) 1878-4380
    ISSN 0966-842X
    DOI 10.1016/j.tim.2022.07.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Geographic Structuring and Divergence Time Frame of Monkeypox Virus in the Endemic Region.

    Forni, Diego / Molteni, Cristian / Cagliani, Rachele / Sironi, Manuela

    The Journal of infectious diseases

    2022  Volume 227, Issue 6, Page(s) 742–751

    Abstract: Background: Monkeypox is an emerging zoonosis endemic to Central and West Africa. Monkeypox virus (MPXV) is genetically structured in 2 major clades (clades 1 and 2/3), but its evolution is poorly explored.: Methods: We retrieved MPXV genomes from ... ...

    Abstract Background: Monkeypox is an emerging zoonosis endemic to Central and West Africa. Monkeypox virus (MPXV) is genetically structured in 2 major clades (clades 1 and 2/3), but its evolution is poorly explored.
    Methods: We retrieved MPXV genomes from public repositories and we analyzed geographic patterns using STRUCTURE. Molecular dating was performed using a using a Bayesian approach.
    Results: We show that the population transmitted in West Africa (clades 2/3) experienced limited drift. Conversely, clade 1 (transmitted in the Congo Basin) possibly underwent a bottleneck or founder effect. Depending on the model used, we estimated that the 2 clades separated ∼560-860 (highest posterior density: 450-960) years ago, a period characterized by expansions and contractions of rainforest areas, possibly creating the ecological conditions for the MPXV reservoir(s) to migrate. In the Congo Basin, MPXV diversity is characterized by 4 subpopulations that show no geographic structuring. Conversely, clades 2/3 are spatially structured with 2 populations located West and East of the Dahomey Gap.
    Conclusions: The distinct histories of the 2 clades may derive from differences in MPXV ecology in West and Central Africa.
    MeSH term(s) Animals ; Monkeypox virus/genetics ; Bayes Theorem ; Mpox (monkeypox)/epidemiology ; Mpox (monkeypox)/genetics ; Africa, Western ; Zoonoses
    Language English
    Publishing date 2022-07-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3019-3
    ISSN 1537-6613 ; 0022-1899
    ISSN (online) 1537-6613
    ISSN 0022-1899
    DOI 10.1093/infdis/jiac298
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Evolutionary history of type II transmembrane serine proteases involved in viral priming.

    Forni, Diego / Sironi, Manuela / Cagliani, Rachele

    Human genetics

    2022  Volume 141, Issue 11, Page(s) 1705–1722

    Abstract: Type II transmembrane serine proteases (TTSPs) are a family of trypsin-like membrane-anchored serine proteases that play key roles in the regulation of some crucial processes in physiological conditions, including cardiac function, digestion, cellular ... ...

    Abstract Type II transmembrane serine proteases (TTSPs) are a family of trypsin-like membrane-anchored serine proteases that play key roles in the regulation of some crucial processes in physiological conditions, including cardiac function, digestion, cellular iron homeostasis, epidermal differentiation, and immune responses. However, some of them, in particular TTSPs expressed in the human airways, were identified as host factors that promote the proteolytic activation and spread of respiratory viruses such as influenza virus, human metapneumovirus, and coronaviruses, including SARS-CoV-2. Given their involvement in viral priming, we hypothesized that members of the TTSP family may represent targets of positive selection, possibly as the result of virus-driven pressure. Thus, we investigated the evolutionary history of sixteen TTSP genes in mammals. Evolutionary analyses indicate that most of the TTSP genes that have a verified role in viral proteolytic activation present signals of pervasive positive selection, suggesting that viral infections represent a selective pressure driving the evolution of these proteases. We also evaluated genetic diversity in human populations and we identified targets of balancing selection in TMPRSS2 and TMPRSS4. This scenario may be the result of an ancestral and still ongoing host-pathogen arms race. Overall, our results provide evolutionary information about candidate functional sites and polymorphic positions in TTSP genes.
    MeSH term(s) Animals ; COVID-19 ; Humans ; Iron ; Mammals ; Membrane Proteins/genetics ; SARS-CoV-2/genetics ; Serine Proteases/genetics ; Trypsin
    Chemical Substances Membrane Proteins ; Iron (E1UOL152H7) ; Serine Proteases (EC 3.4.-) ; Trypsin (EC 3.4.21.4)
    Language English
    Publishing date 2022-02-05
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 223009-4
    ISSN 1432-1203 ; 0340-6717
    ISSN (online) 1432-1203
    ISSN 0340-6717
    DOI 10.1007/s00439-022-02435-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Evolution and diversity of nucleotide and dinucleotide composition in poxviruses.

    Molteni, Cristian / Forni, Diego / Cagliani, Rachele / Bravo, Ignacio G / Sironi, Manuela

    The Journal of general virology

    2023  Volume 104, Issue 10

    Abstract: Poxviruses ( ... ...

    Abstract Poxviruses (family
    MeSH term(s) Animals ; Humans ; Poxviridae/genetics ; Nucleotides ; Codon/genetics ; Evolution, Molecular ; Mammals/genetics ; Dinucleoside Phosphates ; Antiviral Agents
    Chemical Substances Nucleotides ; Codon ; Dinucleoside Phosphates ; Antiviral Agents
    Language English
    Publishing date 2023-10-04
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 219316-4
    ISSN 1465-2099 ; 0022-1317
    ISSN (online) 1465-2099
    ISSN 0022-1317
    DOI 10.1099/jgv.0.001897
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Genetic ancestry and population structure of vaccinia virus.

    Molteni, Cristian / Forni, Diego / Cagliani, Rachele / Clerici, Mario / Sironi, Manuela

    NPJ vaccines

    2022  Volume 7, Issue 1, Page(s) 92

    Abstract: Vaccinia virus (VACV) was used for smallpox eradication, but its ultimate origin remains unknown. The genetic relationships among vaccine stocks are also poorly understood. We analyzed 63 vaccine strains with different origin, as well horsepox virus ( ... ...

    Abstract Vaccinia virus (VACV) was used for smallpox eradication, but its ultimate origin remains unknown. The genetic relationships among vaccine stocks are also poorly understood. We analyzed 63 vaccine strains with different origin, as well horsepox virus (HPXV). Results indicated the genetic diversity of VACV is intermediate between variola and cowpox viruses, and that mutation contributed more than recombination to VACV evolution. STRUCTURE identified 9 contributing subpopulations and showed that the lowest drift was experienced by the ancestry components of Tian Tan and HPXV/Mütter/Mulford genomes. Subpopulations that experienced very strong drift include those that contributed the ancestry of MVA and IHD-W, in good agreement with the very long passage history of these vaccines. Another highly drifted population contributed the full ancestry of viruses sampled from human/cattle infections in Brazil and, partially, to IOC clones, strongly suggesting that the recurrent infections in Brazil derive from the spillback of IOC to the feral state.
    Language English
    Publishing date 2022-08-11
    Publishing country England
    Document type Journal Article
    ISSN 2059-0105
    ISSN (online) 2059-0105
    DOI 10.1038/s41541-022-00519-4
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  10. Article ; Online: Monkeypox virus: The changing facets of a zoonotic pathogen.

    Forni, Diego / Cagliani, Rachele / Molteni, Cristian / Clerici, Mario / Sironi, Manuela

    Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases

    2022  Volume 105, Page(s) 105372

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Humans ; Monkeypox virus/genetics ; Mpox (monkeypox)/epidemiology ; Smallpox ; Africa, Central
    Language English
    Publishing date 2022-10-04
    Publishing country Netherlands
    Document type Review ; Journal Article
    ZDB-ID 2037068-4
    ISSN 1567-7257 ; 1567-1348
    ISSN (online) 1567-7257
    ISSN 1567-1348
    DOI 10.1016/j.meegid.2022.105372
    Database MEDical Literature Analysis and Retrieval System OnLINE

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