De novo mutation rates at the single-mutation resolution in a human HBB gene-region associated with adaptation and genetic disease

While it is known that the mutation rate varies across the genome, previous estimates were based on averaging across various numbers of positions. Here we describe a method to measure the origination rates of target mutations at target base positions and apply it to a 6-bp region in the human hemoglobin subunit beta (HBB) gene and to the identical, paralogous hemoglobin subunit delta (HBD) region in sperm cells from both African and European donors. The HBB region of interest (ROI) includes the site of the hemoglobin S (HbS) mutation, which protects against malaria, is common in Africa and has served as a classic example of adaptation by random mutation and natural selection. We found a significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than in Europeans in the HBB region studied. Finally, the rate of the 20A→T mutation, called the 'HbS mutation' when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations; no instances were observed elsewhere. Further studies will be needed to examine mutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.

A Multi-Agent Motion Prediction and Tracking Method Based on Non-Cooperative Equilibrium

A Multi-Agent Motion Prediction and Tracking method based on non-cooperative equilibrium (MPT-NCE) is proposed according to the fact that some multi-agent intelligent evolution methods, like the MADDPG, lack adaptability facing unfamiliar environments, and are unable to achieve multi-agent motion prediction and tracking, although they own advantages in multi-agent intelligence. Featured by a performance discrimination module using the time difference function together with a random mutation module applying predictive learning, the MPT-NCE is capable of improving the prediction and tracking ability of the agents in the intelligent game confrontation. Two groups of multi-agent prediction and tracking experiments are conducted and the results show that compared with the MADDPG method, in the aspect of prediction ability, the MPT-NCE achieves a prediction rate at more than 90%, which is 23.52% higher and increases the whole evolution efficiency by 16.89%; in the aspect of tracking ability, the MPT-NCE promotes the convergent speed by 11.76% while facilitating the target tracking by 25.85%. The proposed MPT-NCE method shows impressive environmental adaptability and prediction and tracking ability.

Amino acid sites related to the PB2 subunits of IDV affect polymerase activity

Background In 2011, a new influenza virus, named Influenza D Virus (IDV), was isolated from pigs, and then cattle, presenting influenza-like symptoms. IDV is one of the causative agents of Bovine Respiratory Disease (BRD), which causes high morbidity and mortality in feedlot cattle worldwide. To date, the molecular mechanisms of IDV pathogenicity are unknown. Recent IDV outbreaks in cattle, along with serological and genetic evidence of IDV infection in humans, have raised concerns regarding the zoonotic potential of this virus. Influenza virus polymerase is a determining factor of viral pathogenicity to mammals. Methods Here we take a prospective approach to this question by creating a random mutation library about PB2 subunit of the IDV viral polymerase to test which amino acid point mutations will increase viral polymerase activity, leading to increased pathogenicity of the virus. Results Our work shows some exact sites that could affect polymerase activities in influenza D viruses. For example, two single-site mutations, PB2-D533S and PB2-G603Y, can independently increase polymerase activity. The PB2-D533S mutation alone can increase the polymerase activity by 9.92 times, while the PB2-G603Y mutation increments the activity by 8.22 times. Conclusion Taken together, our findings provide important insight into IDV replication fitness mediated by the PB2 protein, increasing our understanding of IDV replication and pathogenicity and facilitating future studies.

Improved wind-driven optimization algorithm for the optimization of hydropower generation from a reservoir

The improvement of reservoir operation optimization (ROO) can lead to comprehensive economic benefits as well as sustainable development of water resources. To achieve this goal, an algorithm named wind-driven optimization (WDO) is first employed for ROO in this paper. An improved WDO(IWDO) is developed by using a dynamic adaptive random mutation mechanism, which can avoid the algorithm stagnation at local optima. Moreover, an adaptive search space reduction (ASSR) strategy that aims at improving the search efficiency of all evolutionary algorithms is proposed. The application results of the Goupitan hydropower station show that IWDO is an effective and viable algorithm for ROO and is capable of obtaining greater power generation compared to the classic WDO. Moreover, it is shown that the ASSR strategy can improve the search efficiency and the quality of scheduling results when coupled with various optimization algorithms such as IWDO, WDO and particle swarm optimization.

Genes used together are more likely to be fused together in evolution by mutational mechanisms: A bioinformatic test of the used-fused hypothesis

Cases of parallel or recurrent gene fusions, whether in evolution or in cancer and genetic disease, are difficult to explain, as they require multiple of the same or similar breakpoints to repeat. The used-together-fused-together hypothesis holds that genes that are used together repeatedly and persistently in a certain context are more likely than otherwise to undergo a fusion mutation in the course of evolution–reminiscent of the Hebbian learning rule where neurons that fire together wire together. This mutational hypothesis offers to explain both evolutionary parallelism and recurrence in disease of gene fusions under one umbrella. Here, we test this hypothesis using bioinformatic data. Various measures of gene interaction, including co-expression, co-localization, same-TAD presence and semantic similarity of GO terms show that human genes whose homologs are fused in one or more other organisms are significantly more likely to interact together than random genes, controlling for genomic distance between genes. In addition, we find a statistically significant overlap between pairs of genes that fused in the course of evolution in non-human species and pairs that undergo fusion in human cancers. These results provide support for the used-together-fused-together hypothesis over several alternative hypotheses, including that all gene pairs can fuse by random mutation, but among pairs that have thus fused, those that have interacted previously are more likely to be favored by selection. Multiple consequences are discussed, including the relevance of mutational mechanisms to exon shuffling, to the distribution of fitness effects of mutation and to parallelism.

The rate and molecular spectrum of mutation are selectively maintained in yeast

What determines the rate (μ) and molecular spectrum of mutation is a fundamental question. The prevailing hypothesis asserts that natural selection against deleterious mutations has pushed μ to the minimum achievable in the presence of genetic drift, or the drift barrier. Here we show that, contrasting this hypothesis, μ substantially exceeds the drift barrier in diverse organisms. Random mutation accumulation (MA) in yeast frequently reduces μ, and deleting the newly discovered mutator gene PSP2 nearly halves μ. These results, along with a comparison between the MA and natural yeast strains, demonstrate that μ is maintained above the drift barrier by stabilizing selection. Similar comparisons show that the mutation spectrum such as the universal AT mutational bias is not intrinsic but has been selectively preserved. These findings blur the separation of mutation from selection as distinct evolutionary forces but open the door to alleviating mutagenesis in various organisms by genome editing.

Enhanced production of extracellular lipase by ethyl methane sulfonate from soil fungal strain in submerged and solid-state fermentation condition

Enhancement in the production of enzyme by utilizing different strains of microbe is one of the main prospects in biotechnology. In the present work, ethyl methane sulfonate (EMF) was selected as the chemical mutagen for inducing mutagenesis in fungi. It is a cheap method to induce random mutation as compared to other methods of recombinant technologies. Strain improvement was done by incubating the fungal spore suspension at variable concentrations of EMS i.e. 4% (v/v) and 10% (v/v) for the time period of 60, 90, and 120 min respectively. The set of control was treated with distilled water only. The fungal colonies were found to be maximum in control plate as compared to the EMF exposed plates. The number of fungal colonies was reduced as we raised the exposure time of EMF. Specific activity and the lipase activity of wild strain and hyperproducer were evaluated under the submerged (SmF) and solid-state fermentation (SSF). The wild strain denoted the 3.2 U/ml/min of enzymatic activity under SmF and 15.87 U/g/min of activity under SSF. In contrast, the best enzymatic activity was represented by S2St1 at 10% of EMS after the time period of 60 min i.e. 11.7 U/ml/min under SmF and 99.35 U/g/min under SSF after the time period of 72 hrs. Statistical analysis by using one-way ANOVA determined that the value of F calculated was lower than the F tabulated. So, there was a significant relation between the EMS percentage and time of exposure among the mutated strains. In conclusion, this soil fungal strain can be utilized to produce lipase enzyme for numerous industrial applications.

CRISPR-Cas, a Revolution in the Treatment and Study of ESKAPE Infections: Pre-Clinical Studies

One of the biggest threats we face globally is the emergence of antimicrobial-resistant (AMR) bacteria, which runs in parallel with the lack in the development of new antimicrobials. Among these AMR bacteria pathogens belonging to the ESKAPE group can be highlighted (Enterococcus spp., Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) due to their profile of drug resistance and virulence. Therefore, innovative lines of treatment must be developed for these bacteria. In this review, we summarize the different strategies for the treatment and study of molecular mechanisms of AMR in the ESKAPE pathogens based on the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) proteins’ technologies: loss of plasmid or cellular viability, random mutation or gene deletion as well directed mutations that lead to a gene’s loss of function.

Three transmission events of Vibrio cholerae O1 into Lusaka, Zambia

Background Cholera has been present and recurring in Zambia since 1977. However, there is a paucity of data on genetic relatedness and diversity of the Vibrio cholerae isolates responsible for these outbreaks. Understanding whether the outbreaks are seeded from existing local isolates or if the outbreaks represent separate transmission events can inform public health decisions. Results Seventy-two V. cholerae isolates from outbreaks in 2009/2010, 2016, and 2017/2018 in Zambia were characterized using multilocus variable number tandem repeat analysis (MLVA) and whole genome sequencing (WGS). The isolates had eight distinct MLVA genotypes that clustered into three MLVA clonal complexes (CCs). Each CC contained isolates from only one outbreak. The results from WGS revealed both clustered and dispersed single nucleotide variants. The genetic relatedness of isolates based on WGS was consistent with the MLVA, each CC was a distinct genetic lineage and had nearest neighbors from other East African countries. In Lusaka, isolates from the same outbreak were more closely related to themselves and isolates from other countries than to isolates from other outbreaks in other years. Conclusions Our observations are consistent with i) the presence of random mutation and alternative mechanisms of nucleotide variation, and ii) three separate transmission events of V. cholerae into Lusaka, Zambia. We suggest that locally, case-area targeted invention strategies and regionally, well-coordinated plans be in place to effectively control future cholera outbreaks.