Identifying Potentially Beneficial Genetic Mutations Associated with Monophyletic Selective Sweep and a Proof-of-Concept Study with Viral Genetic Data

Genetic mutations play a central role in evolution. For a significantly beneficial mutation, a one-time mutation event suffices for the species to prosper and predominate through the process called "monophyletic selective sweep." However, existing methods that rely on counting the number of mutation events to detect selection are unable to find such a mutation in selective sweep. We here introduce a method to detect mutations at the single amino acid/nucleotide level that could be responsible for monophyletic selective sweep evolution. The method identifies a genetic signature associated with selective sweep using the population genetic test statistic Tajima's D We applied the algorithm to ebolavirus, influenza A virus, and severe acute respiratory syndrome coronavirus 2 to identify known biologically significant mutations and unrecognized mutations associated with potential selective sweep. The method can detect beneficial mutations, possibly leading to discovery of previously unknown biological functions and mechanisms related to those mutations.IMPORTANCE In biology, research on evolution is important to understand the significance of genetic mutation. When there is a significantly beneficial mutation, a population of species with the mutation prospers and predominates, in a process called "selective sweep." However, there are few methods that can find such a mutation causing selective sweep from genetic data. We here introduce a novel method to detect such mutations. Applying the method to the genomes of ebolavirus, influenza viruses, and the novel coronavirus, we detected known biologically significant mutations and identified mutations the importance of which is previously unrecognized. The method can deepen our understanding of molecular and evolutionary biology

Simulation study reveals factors that affect the predominance of SARS-CoV-2 novel variant

The novel variants of the SARS-CoV-2 are a great global concern for the ongoing COVID-19 pandemic. However, how the novel variants predominate and replace existing strains remains elusive. In this study, I simulated the infection spread to investigate what kinds of viral, immunological, and epidemiological factors affect the predominance of SARS-CoV-2 novel variants. The results showed that the increase of the transmissibility of the novel variant substantially enhanced the predominance probability. In addition, the increasing trend of the infection spread, the large case number of the epidemic, and the ability of immune escape of the novel variant increased the predominance probability. A small number of cases and a decreasing trend of an entire epidemic, including not only the novel variant but also earlier strains, are especially important to reduce the chance of the predominance of the novel variant and delay the process. Good control of the COVID-19 epidemic could make the disease burden small and sequester the spread of the SARS-CoV-2 novel variants

Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries

Measles, caused by measles virus (MeV), is a common infection in children. MeV is a member of the genus Morbillivirus and is most closely related to rinderpest virus (RPV), which is a pathogen of cattle. MeV is thought to have evolved in an environment where cattle and humans lived in close proximity. Understanding the evolutionary history of MeV could answer questions related to divergence times of MeV and RPV

Evolution of the M gene of the influenza A virus in different host species: large-scale sequence analysis

<p>Abstract</p> <p>Background</p> <p>Influenza A virus infects not only humans, but also other species including avian and swine. If a novel influenza A subtype acquires the ability to spread between humans efficiently, it could cause the next pandemic. Therefore it is necessary to understand the evolutionary processes of influenza A viruses in various hosts in order to gain better knowledge about the emergence of pandemic virus. The virus has segmented RNA genome and 7th segment, M gene, encodes 2 proteins. M1 is a matrix protein and M2 is a membrane protein. The M gene may be involved in determining host tropism. Besides, novel vaccines targeting M1 or M2 protein to confer cross subtype protection have been under development. We conducted the present study to investigate the evolution of the M gene by analyzing its sequence in different species.</p> <p>Results</p> <p>Phylogenetic tree revealed host-specific lineages and evolution rates were different among species. Selective pressure on M2 was stronger than that on M1. Selective pressure on M1 for human influenza was stronger than that for avian influenza, as well as M2. Site-by-site analyses identified one site (amino acid position 219) in M1 as positively selected in human. Positions 115 and 121 in M1, at which consensus amino acids were different between human and avian, were under negative selection in both hosts. As to M2, 10 sites were under positive selection in human. Seven sites locate in extracellular domain. That might be due to host's immune pressure. One site (position 27) positively selected in transmembrane domain is known to be associated with drug resistance. And, two sites (positions 57 and 89) locate in cytoplasmic domain. The sites are involved in several functions.</p> <p>Conclusion</p> <p>The M gene of influenza A virus has evolved independently, under different selective pressure on M1 and M2 among different hosts. We found potentially important sites that may be related to host tropism and immune responses. These sites may be important for evolutional process in different hosts and host adaptation.</p

Helmholtz: A Verifier for Tezos Smart Contracts Based on Refinement Types

27th International Conference, TACAS 2021, Held as Part of the European Joint Conferences on Theory and Practice of Software, ETAPS 2021, Luxembourg City, Luxembourg, March 27 - April 1, 2021Part of the Lecture Notes in Computer Science book series (LNTCS, volume 12652)A smart contract is a program executed on a blockchain, based on which many cryptocurrencies are implemented, and is being used for automating transactions. Due to the large amount of money that smart contracts deal with, there is a surging demand for a method that can statically and formally verify them. This tool paper describes our type-based static verification tool HELMHOLTZ for Michelson, which is a statically typed stack-based language for writing smart contracts that are executed on the blockchain platform Tezos. HELMHOLTZ is designed on top of our extension of Michelson’s type system with refinement types. HELMHOLTZ takes a Michelson program annotated with a user-defined specification written in the form of a refinement type as input; it then typechecks the program against the specification based on the refinement type system, discharging the generated verification conditions with the SMT solver Z3. We briefly introduce our refinement type system for the core calculus Mini-Michelson of Michelson, which incorporates the characteristic features such as compound datatypes (e.g., lists and pairs), higher-order functions, and invocation of another contract. HELMHOLTZ successfully verifies several practical Michelson programs, including one that transfers money to an account and that checks a digital signature

Helmholtz: A Verifier for Tezos Smart Contracts Based on Refinement Types

A smart contract is a program executed on a blockchain, based on which many cryptocurrencies are implemented, and is being used for automating transactions. Due to the large amount of money that smart contracts deal with, there is a surging demand for a method that can statically and formally verify them. This article describes our type-based static verification tool HELMHOLTZ for Michelson, which is a statically typed stack-based language for writing smart contracts that are executed on the blockchain platform Tezos. HELMHOLTZ is designed on top of our extension of Michelson’s type system with refinement types. HELMHOLTZ takes a Michelson program annotated with a user-defined specification written in the form of a refinement type as input; it then typechecks the program against the specification based on the refinement type system, discharging the generated verification conditions with the SMT solver Z3. We briefly introduce our refinement type system for the core calculus Mini-Michelson of Michelson, which incorporates the characteristic features such as compound datatypes (e.g., lists and pairs), higher-order functions, and invocation of another contract. HELMHOLTZ successfully verifies several practical Michelson programs, including one that transfers money to an account and that checks a digital signature

Risk factors for excessive postoperative exo-drift after unilateral lateral rectus muscle recession and medial rectus muscle resection for intermittent exotropia

Background: To detect significant factors associated with excessive postoperative exo-drift in young patients with intermittent exotropia who had undergone unilateral lateral rectus muscle recession and medial rectus muscle resection. Methods: We retrospectively examined the records of 64 consecutive patients Results: Younger patients (P = 0.007), and those with larger preoperative exo-deviation at distance (P = 0.033), a lower incidence of peripheral fusion at distance (P = 0.021) or a greater postoperative initial eso-deviation (P = 0.001), were significantly more likely to have an excessive postoperative exo-drift (> 20 prism diopters). Univariate analysis revealed significant associations between excessive postoperative exo-drift and age at surgery (P = 0.004), preoperative exo-deviation at distance (P = 0.017) and postoperative initial eso-deviation at distance (P Conclusions: Postoperative exodrift in unilateral RR is predicted by the initial postoperative eso-deviation, which may offset the overcorrection. However, the exo-drift is greater in cases with a large preoperative exo-deviation and/or at a younger age, and should be followed carefully

Formulas to Estimate Appropriate Surgical Amounts of Unilateral Recession-Resection in Intermittent Exotropia with Distance-Near Disparity

The purpose of this study was to derive new formulas to provide an optimal surgical procedure and optimal amount of recession-resection (RR) surgery in intermittent exotropia (IXT) with a disparity in angle of deviation depending on the fixation distance. The records of 117 consecutive patients with IXT who underwent RR surgery between March 2008 and December 2011 at Okayama University Hospital were retrospectively examined. Multivariable linear regression analysis was performed using the observed corrective angle of deviation at distance or near fixation as the dependent variable, and amounts of lateral rectus muscle (LR) recession (mm) and medial rectus muscle (MR) resection, and age at surgery (years) as independent variables. Two simultaneous formulas were derived: corrective angle of deviation at distance fixation (°)=1.8×recession (mm)+1.6× resection (mm)+0.15×age (years)–6.6, and corrective angle at near fixation (°)=1.5×recession (mm)+1.7× resection (mm)+0.18×age (years)–3.8. Comparisons of coefficient values of the formulas between distance and near fixation revealed that LR recession was more affected by the corrective angle in distance than near fixation. MR resection was more affected at near than distance fixation. We found that our new formulas estimated the appropriate amount of unilateral RR surgery