Synergism between remdesivir and ribavirin leads to SARS-CoV-2 extinction in cell culture.

BACKGROUND AND PURPOSE: There is a need for effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. The purpose of the present study was to find synergistic antiviral combinations for COVID-19 based on lethal mutagenesis. EXPERIMENTAL APPROACH: The effect of combinations of remdesivir and ribavirin on the infectivity of SARS-CoV-2 in cell culture has been tested. Viral populations were monitored by ultra-deep sequencing, and the decrease of infectivity as a result of the treatment was measured. KEY RESULTS: Remdesivir and ribavirin exerted a synergistic inhibitory activity against SARS-CoV-2, quantified both by CompuSyn (Chou-Talalay method) and Synergy Finder (ZIP-score model). In serial passage experiments, virus extinction was readily achieved with remdesivir-ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi-species. CONCLUSION AND IMPLICATIONS: SARS-CoV-2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS-CoV-2 suppression.

Genetic Variability of Bovine Leukemia Virus: Evidence of Dual Infection, Recombination and Quasi-Species.

We have characterized the intrahost genetic variation in the bovine leukemia virus (BLV) by examining 16 BLV isolates originating from the Western Siberia-Tyumen and South Ural-Chelyabinsk regions of Russia. Our research focused on determining the genetic composition of an 804 bp fragment of the BLV env gene, encoding for the entire gp51 protein. The results provide the first indication of the quasi-species genetic nature of BLV infection and its relevance for genome-level variation. Furthermore, this is the first phylogenetic evidence for the existence of a dual infection with BLV strains belonging to different genotypes within the same host: G4 and G7. We identified eight cases of recombination between these two BLV genotypes. The detection of quasi-species with cases of dual infection and recombination indicated a higher potential of BLV for genetic variability at the intra-host level than was previously considered.

Convergent Evolution Dynamics of SARS-CoV-2 and HIV Surface Envelope Glycoproteins Driven by Host Cell Surface Receptors and Lipid Rafts: Lessons for the Future.

Although very different, in terms of their genomic organization, their enzymatic proteins, and their structural proteins, HIV and SARS-CoV-2 have an extraordinary evolutionary potential in common. Faced with various selection pressures that may be generated by treatments or immune responses, these RNA viruses demonstrate very high adaptive capacities, which result in the continuous emergence of variants and quasi-species. In this retrospective analysis of viral proteins, ensuring the adhesion of these viruses to the plasma membrane of host cells, we highlight many common points that suggest the convergent mechanisms of evolution. HIV and SARS-CoV-2 first recognize a lipid raft microdomain that acts as a landing strip for viral particles on the host cell surface. In the case of mucosal cells, which are the primary targets of both viruses, these microdomains are enriched in anionic glycolipids (gangliosides) forming a global electronegative field. Both viruses use lipid rafts to surf on the cell surface in search of a protein receptor able to trigger the fusion process. This implies that viral envelope proteins are both geometrically and electrically compatible to the biomolecules they select to invade host cells. In the present study, we identify the surface electrostatic potential as a critical parameter controlling the convergent evolution dynamics of HIV-1 and SARS-CoV-2 surface envelope proteins, and we discuss the impact of this parameter on the phenotypic properties of both viruses. The virological data accumulated since the emergence of HIV in the early 1980s should help us to face present and future virus pandemics.

The ensemble of gene regulatory networks at mutation-selection balance.

The evolution of diverse phenotypes both involves and is constrained by molecular interaction networks. When these networks influence patterns of expression, we refer to them as gene regulatory networks (GRNs). Here, we develop a model of GRN evolution analogous to work from quasi-species theory, which is itself essentially the mutation-selection balance model from classical population genetics extended to multiple loci. With this GRN model, we prove that-across a broad spectrum of selection pressures-the dynamics converge to a stationary distribution over GRNs. Next, we show from first principles how the frequency of GRNs at equilibrium is related to the topology of the genotype network, in particular, via a specific network centrality measure termed the eigenvector centrality. Finally, we determine the structural characteristics of GRNs that are favoured in response to a range of selective environments and mutational constraints. Our work connects GRN evolution to quasi-species theory-and thus to classical populations genetics-providing a mechanistic explanation for the observed distribution of GRNs evolving in response to various evolutionary forces, and shows how complex fitness landscapes can emerge from simple evolutionary rules.

Study on the characterization of hepatitis B virus quasi-species based on the long-term cohort study in Long′an County, Guangxi / 中国热带医学

@#Abstract: Objective To clarify the long-term evolution of hepatitis B virus (HBV) quasi-species in HBsAg asymptomatic carriers in Long'an county, Guangxi. Methods ELISA was used to detect serological markers of HBV. Viral loads were measured by real time PCR. HBV DNA was extracted from serum by kits. The whole HBV genome was amplified using nested PCR and amplicons were sequenced by next-generation sequencing (NGS). These sequences from NGS were analyzed by the software like Mega. Results Serum samples were collected from 9 HBsAg asymptomatic carriers in Longan County，Guangxi at 4 different time points in 2004, 2007, 2013, 2019 or 2020. A total of 23 serum samples and 309 full-length gene quasi-species sequences were obtained, with an average amount of (0.18±0.07) G sequencing data for each sample. Genotype of 55.54%(5/9) the studied subjects underwent genotype conversion during the long-term evolution process of HBV quasi-species, and the genotyping results of the phylogenetic tree in the PreS/S region are in perfect agreement with the results of the whole genome analysis; recombinant B/C, I/C were found; the Sn ranged from 0 to 0.37 and the genetic diversity ranged from 0 to 0.11, respectively. A total of 21 special single nucleotide/amino acid mutations (7 in the S region, 2 in the X region, 3 in the PreC region and 9 in the BCP region) and 6 deletion mutations were detected, multiple mutations were found and no drug resistant mutations were found; 77.8%(7/9) of the HBV strains carried by the subjects in 2004 had double mutations at nt1 762(A→T) and 1 764(G→A) and a stop mutation at nt1 896(G→A); HBV mutations can be restored from the mutant type to the wild type and (or) vice versa without antiviral drug pressure, and The evolution rate of HBV genome was 2.03×10-5~3.50×10-3.Conclusion HBV genotype, recombinants, genetic complexity and diversity of HBV quasi-species can change over time during in natural infection. The transformation between HBV mutation type and wild type reduces the value of predicting clinical outcomes by genetic types and related mutations to some extent. The HBV genome evolution rate of asymptomatic carriers of HBsAg in Long'an County is very high.

Epidemiological correlation between COVID-19 epidemic and prevalence of α-1 antitrypsin deficiency in the world.

Among 68 countries in the world, severity of the COVID-19 epidemic was correlated with the prevalence of α-1 antitrypsin (AAT) deficiency. For the severe variant, PI*Z, the correlation coefficient (CC) was 0.8584 for the number of patients and 0.8713 for the number of deaths. For the milder variant, PI*S, it was 0.5818 and 0.6326, respectively. In Japan, the number of patients and deaths correlated with the population size with a CC of 0.6667 and 0.7074 respectively, and was proportional to the population size to the power of 1.65 and 1.54. The prevalence of AAT deficiency also correlated with the epidemiological pattern of COVID-19. In countries with high prevalence of AAT deficiency, after the initial rise, the daily number of patients and that of deaths ran parallel at a high level for more than 6 months without sign of abatement. In countries with a low prevalence of AAT deficiency, after the first wave of the epidemic, the number of the deaths decreased continuously while the number of patients remained the same or even increased resulting in a decreasing case-fatality rate. When the cumulative number of deaths was plotted on the y-axis against the cumulative number of patients on the x-axis, plots fell on a straight line in countries with a high prevalence of AAT deficiency; while in countries with a low prevalence of AAT deficiency, a break appeared, after which the plots fell on flatter slope indicating decreasing case-fatality rate. The observation suggests emergence of an attenuated variant in countries with a low prevalence of AAT deficiency.

Current Developments and Challenges in Plant Viral Diagnostics: A Systematic Review.

Plant viral diseases are the foremost threat to sustainable agriculture, leading to several billion dollars in losses every year. Many viruses infecting several crops have been described in the literature; however, new infectious viruses are emerging frequently through outbreaks. For the effective treatment and prevention of viral diseases, there is great demand for new techniques that can provide accurate identification on the causative agents. With the advancements in biochemical and molecular biology techniques, several diagnostic methods with improved sensitivity and specificity for the detection of prevalent and/or unknown plant viruses are being continuously developed. Currently, serological and nucleic acid methods are the most widely used for plant viral diagnosis. Nucleic acid-based techniques that amplify target DNA/RNA have been evolved with many variants. However, there is growing interest in developing techniques that can be based in real-time and thus facilitate in-field diagnosis. Next-generation sequencing (NGS)-based innovative methods have shown great potential to detect multiple viruses simultaneously; however, such techniques are in the preliminary stages in plant viral disease diagnostics. This review discusses the recent progress in the use of NGS-based techniques for the detection, diagnosis, and identification of plant viral diseases. New portable devices and technologies that could provide real-time analyses in a relatively short period of time are prime important for in-field diagnostics. Current development and application of such tools and techniques along with their potential limitations in plant virology are likewise discussed in detail.

Quasi-species evolution maximizes genotypic reproductive value (not fitness or flatness).

Growing efforts to measure fitness landscapes in molecular and microbial systems are motivated by a longstanding goal to predict future evolutionary trajectories. Sometimes under-appreciated, however, is that the fitness landscape and its topography do not by themselves determine the direction of evolution: under sufficiently high mutation rates, populations can climb the closest fitness peak (survival of the fittest), settle in lower regions with higher mutational robustness (survival of the flattest), or even fail to adapt altogether (error catastrophes). I show that another measure of reproductive success, Fisher's reproductive value, resolves the trade-off between fitness and robustness in the quasi-species regime of evolution: to forecast the motion of a population in genotype space, one should look for peaks in the (mutation-rate dependent) landscape of genotypic reproductive values-whether or not these peaks correspond to local fitness maxima or flat fitness plateaus. This new landscape picture turns quasi-species dynamics into an instance of non-equilibrium dynamics, in the physical sense of Markovian processes, potential landscapes, entropy production, etc.

Natural Defect of a Plant Rhabdovirus Glycoprotein Gene: A Case Study of Virus-Plant Coevolution.

Seven isolates of a putative cytorhabdovirus (family Rhabdoviridae, order Mononegavirales) designated as citrus-associated rhabdovirus (CiaRV) were identified in citrus, passion fruit, and paper bush from the same geographical area in China. CiaRV, bean-associated cytorhabdovirus (Brazil), and papaya virus E (Ecuador) should be taxonomically classified in the species Papaya cytorhabdovirus. Due to natural mutations, the glycoprotein (G) and P4 genes were impaired in citrus-infecting isolates of CiaRV, resulting in an atypical rhabdovirus genome organization of 3' leader-N-P-P3-M-L-5' trailer. The P3 protein of CiaRV shared a common origin with begomoviral movement proteins (family Geminiviridae). Secondary structure analysis and trans-complementation of movement-deficient tomato mosaic virus and potato virus X mutants by CiaRV P3 supported its function in viral cell-to-cell trafficking. The wide geographical dispersal of CiaRV and related viruses suggests an efficient transmission mechanism, as well as an underlying risk to global agriculture. Both the natural phenomenon and experimental analyses demonstrated presence of the "degraded" type of CiaRV in citrus, in parallel to "undegraded" types in other host plant species. This case study shows a plant virus losing the function of an important but nonessential gene, likely due to host shift and adaption, which deepened our understanding of course of natural viral diversification.

Insights Into Potato Spindle Tuber Viroid Quasi-Species From Infection to Disease.

Viroids are non-coding RNA plant pathogens that are characterized by their possession of a high mutation level. Although the sequence heterogeneity in viroid infected plants is well understood, shifts in viroid population dynamics due to mutations over the course of infection remain poorly understood. In this study, the ten most abundant sequence variants of potato spindle tuber viroid RG1 (PSTVd) expressed at different time intervals in PSTVd infected tomato plants were identified by high-throughput sequencing. The sequence variants, forming a quasi-species, were subjected to both the identification of the regions favoring mutations and the effect of the mutations on viroid secondary structure and viroid derived small RNAs (vd-sRNA). At week 1 of PSTVd infection, 25% of the sequence variants were similar to the "master" sequence (i.e., the sequence used for inoculation). The frequency of the master sequence within the population increased to 70% at week 2 after PSTVd infection, and then stabilized for the rest of the disease cycle (i.e., weeks 3 and 4). While some sequence variants were abundant at week 1 after PSTVd infection, they tended to decrease in frequency over time. For example, the variants with insertions at positions 253 or 254, positions that could affect the Loop E as well as the metastable hairpin I structure that has been shown important during replication and viroid infectivity, resulted in decreased frequency. Data obtained by in silico analysis of the viroid derived small RNAs (vd-sRNA) was also analyzed. A few mutants had the potential of positively affecting the viroid's accumulation by inducing the RNA silencing of the host's defense related genes. Variants with mutations that could negatively affect viroid abundance were also identified because their derived vd-sRNA were no longer capable of targeting any host mRNA or of changing its target sequence from a host defense gene to some other non-important host gene. Together, these findings open avenues into understanding the biological role of sequence variants, this viroid's interaction with host components, stable and metastable structures generated by mutants during the course of infection, and the influence of sequence variants on stabilizing viroid population dynamics.

Characterization of Plaque Variants and the Involvement of Quasi-Species in a Population of EV-A71.

Viral plaque morphologies in human cell lines are markers for growth capability and they have been used to assess the viral fitness and selection of attenuated mutants for live-attenuated vaccine development. In this study, we investigate whether the naturally occurring plaque size variation reflects the virulence of the variants of EV-A71. Variants of two different plaque sizes (big and small) from EV-A71 sub-genotype B4 strain 41 were characterized. The plaque variants displayed different in vitro growth kinetics compared to the parental wild type. The plaque variants showed specific mutations being present in each variant strain. The big plaque variants showed four mutations I97L, N104S, S246P and N282D in the VP1 while the small plaque variants showed I97T, N237T and T292A in the VP1. No other mutations were detected in the whole genome of the two variants. The variants showed stable homogenous small plaques and big plaques, respectively, when re-infected in rhabdomyosarcoma (RD) and Vero cells. The parental strain showed faster growth kinetics and had higher viral RNA copy number than both the big and small plaque variants. Homology modelling shows that both plaque variants have differences in the structure of the VP1 protein due to the presence of unique spontaneous mutations found in each plaque variant This study suggests that the EV-A71 sub-genotype B4 strain 41 has at least two variants with different plaque morphologies. These differences were likely due to the presence of spontaneous mutations that are unique to each of the plaque variants. The ability to maintain the respective plaque morphology upon passaging indicates the presence of quasi-species in the parental population.

Whole-Genome Deep Sequencing Reveals Host-Driven in-planta Evolution of Columnea Latent Viroid (CLVd) Quasi-Species Populations.

Columnea latent viroid (CLVd) is one of the most serious tomato diseases. In general, viroids have high mutation rates. This generates a population of variants (so-called quasi-species) that co-exist in their host and exhibit a huge level of genetic diversity. To study the population of CLVd in individual host plants, we used amplicon sequencing using specific CLVd primers linked with a sample-specific index sequence to amplify libraries. An infectious clone of a CLVd isolate Chaipayon-1 was inoculated on different solanaceous host plants. Six replicates of the amplicon sequencing results showed very high reproducibility. On average, we obtained 133,449 CLVd reads per PCR-replicate and 79 to 561 viroid sequence variants, depending on the plant species. We identified 19 major variants (>1.0% mean relative abundance) in which a total of 16 single-nucleotide polymorphisms (SNPs) and two single nucleotide insertions were observed. All major variants contained a combination of 4 to 6 SNPs. Secondary structure prediction clustered all major variants into a tomato/bolo maka group with four loops (I, II, IV and V), and a chili pepper group with four loops (I, III, IV and V) at the terminal right domain, compared to the CLVd Chaipayon-1 which consists of five loops (I, II, III, IV and V).

Long-term passage of duck Tembusu virus in BHK-21 cells generates a completely attenuated and immunogenic population with increased genetic diversity.

Duck Tembusu virus (TMUV) is an emerging pathogenic flavivirus that causes severe egg-drop and fatal encephalitis in domestic ducks and geese. Although a live-attenuated virus vaccine is effective for disease control, the stability of the attenuation has not been clearly evaluated due to a poor understanding of the attenuation mechanism. Here, a virulent duck TMUV isolate was successively passaged in BHK-21 cells, leading to an approximately 100-fold increase of virus production in cell culture and a complete attenuation of virulence for ducks. The passaged virus induced high titers of TMUV-specific antibody and provided efficient protection against a virulent TMUV challenge after a single-dose vaccination. One hundred and two, and eighteen single-nucleotide polymorphisms (SNPs) at a frequency of >1% were respectively identified in the attenuated virus population and the original isolate by deep sequencing. The increased SNPs numbers suggested that the accumulated variants of virus population may have conferred the phenotypic changes. We cloned and characterized a dominant variant exhibiting similar fitness to the mixed population, and 23 amino acid substitutions were identified across the viral open reading frame. Using reverse genetics, two chimeric viruses were generated by introducing the mutated E or NS5 gene into the backbone of virulent TMUV. We found that mutations in the E gene conferred a fitness advantage in BHK-21 cells and decreased the virus pathogenicity, whereas NS5 mutations reduced the virus infectivity in ducklings without altering the in vitro fitness. In conclusion, increased mutations in a virulent TMUV strain did substantially reduce the virus virulence, and mutations in multiple genes co-contribute to TMUV attenuation.

The inference of HIV-1 transmission direction between HIV-1 positive couples based on the sequences of HIV-1 quasi-species.

BACKGROUND: To infer transmission direction of a HIV transmission chain is helpful not only in legal jurisdiction but also in precise intervention to prevent HIV spread. Recently, the direction of transmission is inferred by whether paraphyletic-monophyletic (PM) or a combination of paraphyletic and polyphyletic (PP) topologies is observed or not between the sequences of source and recipient in the phylogenetic tree. However, paraphyly between them often declines over time and may disappear between spouses due to bidirectional transmission after primary infection. In this study, our aim is to test the reliability of inferring HIV transmission direction between epidemiologically linked HIV-1 positive couples using whether or not paraphyly is observed in phylogenetic tree. METHODS: HIV quasi-species were sequenced using PCR product clones, and then Bayesian analysis of molecular sequences with MCMC was employed to construct phylogenetic relationship of env, gag, pol gene fragments of HIV-1 positive couples using BEAST software. RESULTS: Our results showed that all sequences of seven couples except pol sequences of couple 12 and 13 form their own monophyletic cluster in phylogenetic tree including the closest control sequences from GenBank or other studies on local samples, which are supported by significant Bayesian posterior probabilities more than 0.9932. Of seven couples, paraphyly is only observed in phylogenetic tree constructed with env and pol gene sequences of three couples and gag gene sequences of four couples. Paraphyly is not observed in half of HIV positive couples. Pol sequences of couple 13 is separated by Blast selected controls; pol sequences of couple 12 in phylogenetic tree is supported by a lower Bayesian posterior value. CONCLUSION: Paraphyly relationship between sequences of donator and recipient is only observed among partial HIV-1 positive couples with epidemiological link. Phylogenetic relationship is not always the same when various gene regions of HIV are used to conduct phylogenetic analysis. The combination of phylogenetic analysis based on various gene regions of HIV and enough epidemiology investigation is essential when inferring transmission direction of HIV in a transmission chain or in one couple. However, while observed paraphyly can be used to infer transmission direction in HIV-1 positive couple, no observed paraphyly cannot deny it.

Heterogeneity and Architecture of Pathological Prion Protein Assemblies: Time to Revisit the Molecular Basis of the Prion Replication Process?

Prions are proteinaceous infectious agents responsible for a range of neurodegenerative diseases in animals and humans. Prion particles are assemblies formed from a misfolded, ß-sheet rich, aggregation-prone isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Prions replicate by recruiting and converting PrPC into PrPSc, by an autocatalytic process. PrPSc is a pleiomorphic protein as different conformations can dictate different disease phenotypes in the same host species. This is the basis of the strain phenomenon in prion diseases. Recent experimental evidence suggests further structural heterogeneity in PrPSc assemblies within specific prion populations and strains. Still, this diversity is rather seen as a size continuum of assemblies with the same core structure, while analysis of the available experimental data points to the existence of structurally distinct arrangements. The atomic structure of PrPSc has not been elucidated so far, making the prion replication process difficult to understand. All currently available models suggest that PrPSc assemblies exhibit a PrPSc subunit as core constituent, which was recently identified. This review summarizes our current knowledge on prion assembly heterogeneity down to the subunit level and will discuss its importance with regard to the current molecular principles of the prion replication process.

[17th plant virology meeting report]. / Compte rendu des 17es Rencontres de virologie végétale.

RVV Plant virology meeting (January 27-31, 2019, Aussois, France) allows researchers, engineers, technicians, students and post-docs to exchange around oral and poster presentations. These convivial meetings are 30 years old and have a nice future.

Nanopore sequencing and full genome de novo assembly of human cytomegalovirus TB40/E reveals clonal diversity and structural variations.

BACKGROUND: Human cytomegalovirus (HCMV) has a double-stranded DNA genome of approximately 235 Kbp that is structurally complex including extended GC-rich repeated regions. Genomic recombination events are frequent in HCMV cultures but have also been observed in vivo. Thus, the assembly of HCMV whole genomes from technologies producing shorter than 500 bp sequences is technically challenging. Here we improved the reconstruction of HCMV full genomes by means of a hybrid, de novo genome-assembly bioinformatics pipeline upon data generated from the recently released MinION MkI B sequencer from Oxford Nanopore Technologies. RESULTS: The MinION run of the HCMV (strain TB40/E) library resulted in ~ 47,000 reads from a single R9 flowcell and in ~ 100× average read depth across the virus genome. We developed a novel, self-correcting bioinformatics algorithm to assemble the pooled HCMV genomes in three stages. In the first stage of the bioinformatics algorithm, long contigs (N50 = 21,892) of lower accuracy were reconstructed. In the second stage, short contigs (N50 = 5686) of higher accuracy were assembled, while in the final stage the high quality contigs served as template for the correction of the longer contigs resulting in a high-accuracy, full genome assembly (N50 = 41,056). We were able to reconstruct a single representative haplotype without employing any scaffolding steps. The majority (98.8%) of the genomic features from the reference strain were accurately annotated on this full genome construct. Our method also allowed the detection of multiple alternative sub-genomic fragments and non-canonical structures suggesting rearrangement events between the unique (UL /US) and the repeated (T/IRL/S) genomic regions. CONCLUSIONS: Third generation high-throughput sequencing technologies can accurately reconstruct full-length HCMV genomes including their low-complexity and highly repetitive regions. Full-length HCMV genomes could prove crucial in understanding the genetic determinants and viral evolution underpinning drug resistance, virulence and pathogenesis.

Within-Host Recombination in the Foot-and-Mouth Disease Virus Genome.

Recombination is one of the determinants of genetic diversity in the foot-and-mouth disease virus (FMDV). FMDV sequences have a mosaic structure caused by extensive intra- and inter-serotype recombination, with the exception of the capsid-encoding region. While these genome-wide patterns of broad-scale recombination are well studied, not much is known about the patterns of recombination that may exist within infected hosts. In addition, detection of recombination among viruses evolving at the within-host level is challenging due to the similarity of the sequences and the limitations in differentiating recombination from point mutations. Here, we present the first analysis of recombination events between closely related FMDV sequences occurring within buffalo hosts. The detection of these events was made possible by the occurrence of co-infection of two viral swarms with about 1% nucleotide divergence. We found more than 15 recombination events, unequally distributed across eight samples from different animals. The distribution of these events along the FMDV genome was neither uniform nor related to the phylogenetic distribution of recombination breakpoints, suggesting a mismatch between within-host evolutionary pressures and long-term selection for infectivity and transmissibility.

Trans-heteroclinic bifurcation: a novel type of catastrophic shift.

Global and local bifurcations are extremely important since they govern the transitions between different qualitative regimes in dynamical systems. These transitions or tipping points, which are ubiquitous in nature, can be smooth or catastrophic. Smooth transitions involve a continuous change in the steady state of the system until the bifurcation value is crossed, giving place to a second-order phase transition. Catastrophic transitions involve a discontinuity of the steady state at the bifurcation value, giving place to first-order phase transitions. Examples of catastrophic shifts can be found in ecosystems, climate, economic or social systems. Here we report a new type of global bifurcation responsible for a catastrophic shift. This bifurcation, identified in a family of quasi-species equations and named as trans-heteroclinic bifurcation, involves an exchange of stability between two distant and heteroclinically connected fixed points. Since the two fixed points interchange the stability without colliding, a catastrophic shift takes place. We provide an exhaustive description of this new bifurcation, also detailing the structure of the replication-mutation matrix of the quasi-species equation giving place to this bifurcation. A perturbation analysis is provided around the bifurcation value. At this value the heteroclinic connection is replaced by a line of fixed points in the quasi-species model. But it is shown that, if the replication-mutation matrix satisfies suitable conditions, then, under a small perturbation, the exchange of heteroclinic connections is preserved, except on a tiny range around the bifurcation value whose size is of the order of magnitude of the perturbation. The results presented here can help to understand better novel mechanisms behind catastrophic shifts and contribute to a finer identification of such transitions in theoretical models in evolutionary biology and other dynamical systems.