The soil bacterium Burkholderia pseudomallei is the causative agent of melioidosis and a significant cause of human morbidity and mortality in many tropical and subtropical countries. The species notoriously survives harsh environmental conditions but the genetic architecture for these adaptations remains unclear. Here we employed a powerful combination of genome-wide epistasis and co-selection studies (2,011 genomes), condition-wide transcriptome analyses (82 diverse conditions), and a gene knockout assay to uncover signals of “co-selection”—that is a combination of genetic markers that have been repeatedly selected together through B. pseudomallei evolution. These enabled us to identify 13,061 mutation pairs under co-selection in distinct genes and noncoding RNA. Genes under co-selection displayed marked expression correlation when B. pseudomallei was subjected to physical stress conditions, highlighting the conditions as one of the major evolutionary driving forces for this bacterium. We identified a putative adhesin (BPSL1661) as a hub of co-selection signals, experimentally confirmed a BPSL1661 role under nutrient deprivation, and explored the functional basis of co-selection gene network surrounding BPSL1661 in facilitating the bacterial survival under nutrient depletion. Our findings suggest that nutrient-limited conditions have been the common selection pressure acting on this species, and allelic variation of BPSL1661 may have promoted B. pseudomallei survival during harsh environmental conditions by facilitating bacterial adherence to different surfaces, cells, or living hosts.
Identification of novel photosynthetic proteins is important for understanding and improving photosynthetic efficiency. Synergistically, genome neighborhood can provide additional useful information to identify photosynthetic proteins. We, therefore, expected that applying a computational approach, particularly machine learning (ML) with the genome neighborhood-based feature should facilitate the photosynthetic function assignment. Our results revealed a functional relationship between photosynthetic genes and their conserved neighboring genes observed by ‘Phylo score’, indicating their functions could be inferred from the genome neighborhood profile. Therefore, we created a new method for extracting patterns based on the genome neighborhood network (GNN) and applied them for the photosynthetic protein classification using ML algorithms. Random forest (RF) classifier using genome neighborhood-based features achieved the highest accuracy up to 87% in the classification of photosynthetic proteins and also showed better performance (Mathew’s correlation coefficient = 0.718) than other available tools including the sequence similarity search (0.447) and ML-based method (0.361). Furthermore, we demonstrated the ability of our model to identify novel photosynthetic proteins compared to the other methods. Our classifier is available at http://bicep2.kmutt.ac.th/photomod_standalone, https://bit.ly/2S0I2Ox and DockerHub: https://hub.docker.com/r/asangphukieo/photomod.
Cyclotides are a family of triple disulfide cyclic peptides with exceptional resistance to thermal/chemical denaturation and enzymatic degradation. Several cyclotides have been shown to possess anti-HIV activity, including kalata B1 (KB1). However, the use of cyclotides as anti-HIV therapies remains limited due to the high toxicity in normal cells. Therefore, grafting anti-HIV epitopes onto a cyclotide might be a promising approach for reducing toxicity and simultaneously improving anti-HIV activity. Viral envelope glycoprotein gp120 is required for entry of HIV into CD4+ T cells. However, due to a high degree of variability and physical shielding, the design of drugs targeting gp120 remains challenging. We created a computational protocol in which molecular modeling techniques were combined with a genetic algorithm (GA) to automate the design of new cyclotides with improved binding to HIV gp120. We found that the group of modified cyclotides has better binding scores (23.1%) compared to the KB1. By using molecular dynamic (MD) simulation as a post filter for the final candidates, we identified two novel cyclotides, GA763 and GA190, which exhibited better interaction energies (36.6% and 22.8%, respectively) when binding to gp120 compared to KB1. This computational design represents an alternative tool for modifying peptides, including cyclotides and other stable peptides, as therapeutic agents before the synthesis process.
The soil bacterium Burkholderia pseudomallei is the causative agent of melioidosis and a significant cause of human morbidity and mortality in many tropical and sub-tropical countries. The species notoriously survives harsh environmental conditions but the genetic architecture for these adaptations remains unclear. Here we employed a powerful combination of genome-wide epistasis and co-selection studies, gene expression analysis, and gene knockout assays to uncover genetic markers that have been repeatedly selected through B. pseudomallei evolution. These enabled us to identify a large number of mutation pairs under co-selection in distinct genes and non-coding RNA, of which a majority (61.5%) of signals detected in the discovery dataset can be replicated in the validation dataset (totalling 2,011 genomes). Genes under co-selection are mostly conditionally expressed with marked expression correlation of gene-gene pairs found in physical stress conditions. We discovered a putative adhesin (BPSL1661) as a hub of co-selection signals and experimentally confirmed the essential role of BPSL1661 under nutrient deprivation. The gene co-selection network surrounding BPSL1661 likely offers B. pseudomallei a selective advantage to survive nutrient limited conditions. We propose that anthropogenic activities such as pre- and post-harvest crop residue burning have accelerated soil nutrient depletion and may have directly contributed to the preferential survival of B. pseudomallei over benign soil microorganisms. This is expected to lead to a consequent increase in the incidence of melioidosis should the slash-and-burn practices continue to expand.
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