Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Analysis of mobile genetic elements in the genomes of Bacillus thuringiensis and Bacillus cereus

Bacillus cereus sensu lato is an ecologically diverse bacterial group that comprises nine phylogenetically close species. Its three most studied members are B. thuringiensis, the worldwide biopesticide, B. cereus sensu stricto, the potential human foodborne pathogen and B. anthracis, the causative agent of anthrax, a potential “biological weapon”. This group holds a collection of mobile genetic elements (MGE) that include toxin-carrying and conjugative plasmids, and transposable elements such as insertion sequences (IS) or class II transposons. Some of these elements are very well studied, whereas others remain uncharted, as is the case of IS982, a family that was reviewed within this manuscript. Globally, in the course of this work, the distribution of MGE as well as the mobile DNA-based genome plasticity of the B. cereus group were probed, with a particular focus on B. thuringiensis, its entomopathogenic member. In this scope, the first objective was to analyze four distinct types of mobile genetic elements including IS, Class II transposons of the Tn3 family, group II introns and B. cereus repeats (bcr), in 102 completely sequenced genomes of nine B. cereus s.l. species via a bioinformatics approach. Our study shows, not only the variable distribution of MGE between species, but also among strains of the same species. Moreover, our results reveal the existence of significant correlations between bcr pairs, whose variation between species could be used as an additional parameter to whole genome-based phylogenetic approaches. Furthermore, this work highlights the potential impact of these MGE elements on the plasmid pool, particularly the toxin-carrying plasmids of B. thuringiensis, key players in its entomopathogenic capacities. The focus was then set on B. thuringiensis with the characterization of novel mosquitocidal strains, isolated from Lebanese soil, by in-depth analysis of the strains’ genomes, toxin-carrying plasmids and parasporal crystal proteins content. Two strains, AR23 and H3, highly toxic and displaying unusual killing activities, and plasmid and crystal protein profiles, were probed for the toxin-coding genes they carry, their MGE repertoire and possible interconnection between virulence and genome plasticity. AR23 belongs to B. thuringiensis sv. israelensis, whose mobile DNA pool was extensively reviewed in the introduction of this thesis. However, AR23 is more toxic than the reference AM65-52 for three mosquito species, most likely thanks to an additional functional copy of cry4Ba gene and a simplified plasmid content. As for H3, it is a non-cytolytic B. thuringiensis strain, active against mosquito larvae but at higher doses than the reference strain AM65-52. Analysis of this strain uncovered the novel Cry toxins it produces, four of which have an unusual ORF1-gap-ORF2 organization. H3 toxin-coding genes are also located in a highly dynamic plasmid environment with three novel mega-plasmids and a wealth of transposable elements. In summary, his study highlighted the distribution and the importance of MGE within B. cereus group and particularly that of B. thuringiensis active against Dipteran larvae.(AGRO - Sciences agronomiques et ingénierie biologique) -- UCL, 202

IS 982 and kin: new insights into an old IS family.

Insertion sequences (IS) are ubiquitous transposable elements with a very simple organization: two inverted repeats flanking a transposase coding gene. IS is one of 26 insertion sequence families known so far. With 70 registered members in the ISFinder database, this family remains somewhat unexplored, despite the association of many of its members with important features such as antibiotic resistance. IS has a fairly simple organization with a mean length of ca. 1 Kb, two inverted repeats with conserved 5' AC 3' ends flanking a transposase coding gene and direct repeats of variable lengths. Its transposase has a RNAse-H like chemistry with an atypical DDE motif. In this study, we first highlight the current knowledge on the IS family by dissecting its registered members and their characteristics. Secondly, we bring new insights into this old, yet uncharted IS family, by exploring its registered elements, as well as the genomic and proteomic databases of bacterial and archaeal strains. This probing showed that the presence and distribution of this family goes far beyond the clear-cut registry of ISFinder database

Diversity of Bacillus cereus sensu lato mobilome

Bacillus cereus sensu lato s.l.) is a group of bacteria displaying close phylogenetic relationships but a high ecological diversity. The three most studied species are Bacillus anthracis, Bacillus cereus sensu stricto and Bacillus thuringiensis. While some species are pathogenic to mammals or associated with food poisoning, Bacillus thuringiensis is a well-known entomopathogenic bacterium used as biopesticide worldwide. B. cereus s.l. also contains a large variety of mobile genetic elements (MGEs)

Conjugation across Bacillus cereus and kin: A review

Horizontal gene transfer (HGT) is a major driving force in shaping bacterial communities. Key elements responsible for HGT are conjugation-like events and transmissible plasmids. Conjugative plasmids can promote their own transfer as well as that of co-resident plasmids. Bacillus cereus and relatives harbor a plethora of plasmids, including conjugative plasmids, which are at the heart of the group species differentiation and specification. Since the first report of a conjugation-like event between strains of B. cereus sensu lato (s.l.) 40 years ago, many have studied the potential of plasmid transfer across the group, especially for plasmids encoding major toxins. Over the years, more than 20 plasmids from B. cereus isolates have been reported as conjugative. However, with the increasing number of genomic data available, in silico analyses indicate that more plasmids from B. cereus s.l. genomes present self-transfer potential. B. cereus s.l. bacteria occupy diverse environmental niches, which were mimicked in laboratory conditions to study conjugation-related mechanisms. Laboratory mating conditions remain nonetheless simplistic compared to the complex interactions occurring in natural environments. Given the health, economic and ecological importance of strains of B. cereus s.l., it is of prime importance to consider the impact of conjugation within this bacterial group

Bacillus cytotoxicus Genomics: Chromosomal Diversity and Plasmidome Versatility

Bacillus cytotoxicus is the thermotolerant representative of the Bacillus cereus group. This group, also known as B. cereus sensu lato, comprises both beneficial and pathogenic members and includes psychrotolerant and thermotolerant species. Bacillus cytotoxicus was originally recovered from a fatal outbreak in France in 1998. This species forms a remote cluster from the B. cereus group members and reliably contains the cytk-1 gene, coding for a cytotoxic variant of cytotoxin K. Although this species was originally thought to be homogenous, intra-species diversity has been recently described with four clades, six random amplified polymorphic DNA (RAPD) patterns, and 11 plasmids profiles. This study aimed to get new insights into the genomic diversity of B. cytotoxicus and to decipher the underlying chromosomal and plasmidial variations among six representative isolates through whole genome sequencing (WGS). Among the six sequenced strains, four fitted the previously described genomic clades A and D, while the remaining two constituted new distinct branches. As for the plasmid content of these strains, three large plasmids were putatively conjugative and three small ones potentially mobilizable, harboring coding genes for putative leaderless bacteriocins. Mobile genetic elements, such as prophages, Insertion Sequences (IS), and Bacillus cereus repeats (bcr) greatly contributed to the B. cytotoxicus diversity. As for IS elements and bcr, IS3 and bcr1 were the most abundant elements and, along with the group II intron B.c.I8, were found in all analyzed B. cytotoxicus strains. When compared to other B. cytotoxicus strains, the type-strain NVH 391-98 displayed a relatively low number of IS. Our results shed new light on the contribution of mobile genetic elements to the genome plasticity of B. cytotoxicus and their potential role in horizontal gene transfer

pXO16, the large conjugative plasmid from Bacillus thuringiensis serovar israelensis displays an extended host spectrum

pXO16, the large conjugative plasmid from Bacillus thuringiensis serovar israelensis is able to efficient self-transfer, to mobilize and retro-mobilize non-conjugative plasmids, including "non-mobilizable" plasmids, and to transfer chromosomal loci. It also displays a remarkable aggregation phenotype associated with conjugation under liquid conditions. However, it was recently shown that aggregation boosts pXO16 transfer but is not mandatory. In this paper, we have further explored pXO16 transfers under various mating conditions and with different members of the Bacillus cereus group. The results indicated that colony or filter mating largely compensate the transfer deficit observed when using a pXO16 aggregation-minus mutant. Using filter mating, pXO16 transfer efficiency and host range were both improved. For instance, pXO16 was shown to transfer itself, and to mobilize the small pUB110 plasmid, from B. thuringiensis serovar israelensis to the thermotolerant Bacillus cytotoxicus at frequencies of 3.3 × 10-3 and 5.2 × 10-4 transconjugants per donor (T/D), respectively. All together, these results indicate that pXO16 can potentially "circulate" among members of the Bacillus cereus group. Yet, this is contrasting with pXO16's known natural distribution, which is apparently limited to the israelensis serovar of B. thuringiensis

Optimization of Culture Conditions and Wheat Bran Class Selection in the Production of Bacillus thuringiensis-Based Biopesticides

International audienceBacillus thuringiensis is the leading microbial-based biopesticide, thanks to its parasporal crystal proteins or δ-endotoxins, which are toxic to insect larvae upon ingestion. Once in the insect larvae midgut, the crystal is solubilized by the alkaline pH and the δ-endotoxins activated by proteolytic cleavage. Thanks to its high efficiency as a biopesticide, several efforts have been made to enhance its growth and δ-endotoxins production, in various types of culture media. In this study, a culture medium based on wheat bran (WB), the by-product of cereal grain milling, was used to grow Bacillus thuringiensis and produce δ-endotoxins. Using the response surface methodology (RSM), the effects of three variables were evaluated: WB particles granulometry, their concentration, and their agitation in a 48-h shake-flask culture at 30 °C. Three response parameters were targeted: δ-endotoxins production, final culture pH, and dry-matter consumption. According to the RSM results, the optimum would be at 3.7 g WB/50 mL, with a granulometry above 680 μm and agitation between 170 and 270 rpm. This study is key to developing natural and cheap culture media that can be used at an industrial level for Bacillus thuringiensis-based biopesticides

A Novel Antidipteran Bacillus thuringiensis Strain: Unusual Cry Toxin Genes in a Highly Dynamic Plasmid Environment

Bacillus thuringiensis has emerged as a major bioinsecticide on the global market. It offers a valuable alternative to chemical products classically utilized to control pest insects. Despite the efficiency of several strains and products available on the market, the scientific community is always on the lookout for novel toxins that can replace or supplement the existing products. In this study, H3, a novel B. thuringiensis strain showing mosquitocidal activity, was isolated from Lebanese soil and characterized in vivo at genomic and proteomic levels. H3 parasporal crystal is toxic on its own but displays an unusual killing profile with a higher 50% lethal concentration (LC50) than the reference B. thuringiensis serovar israelensis crystal proteins. In addition, H3 has a different toxicity order: it is more toxic to Aedes albopictus and Anopheles gambiae than to Culex pipiens. Whole-genome sequencing and crystal analysis revealed that H3 can produce 11 novel Cry proteins, 8 of which are assembled in genes with an orf1-gap-orf2 organization, where orf2 is a potential Cry4-type crystallization domain. Moreover, pH3-180, the toxin-carrying plasmid, holds a wide repertoire of mobile genetic elements that amount to ca. 22% of its size., including novel insertion sequences and class II transposable elements. Two other large plasmids present in H3 carry genetic determinants for the production of many interesting molecules—such as chitinase, cellulase, and bacitracin—that may add up to H3 bioactive properties. This paper therefore reports a novel mosquitocidal Bacillus thuringiensis strain with unusual Cry toxin genes in a rich mobile DNA environment