Types Of Gene Clusters Research Articles

Zol & fai: large-scale targeted detection and evolutionary investigation of gene clusters.

Many universally and conditionally important genes are genomically aggregated within clusters. Here, we introduce fai and zol, which together enable large-scale comparative analysis of different types of gene clusters and mobile-genetic elements (MGEs), such as biosynthetic gene clusters (BGCs) or viruses. Fundamentally, they overcome a current bottleneck to reliably perform comprehensive orthology inference at large scale across broad taxonomic contexts and thousands of genomes. First, fai allows the identification of orthologous instances of a query gene cluster of interest amongst a database of target genomes. Subsequently, zol enables reliable, context-specific inference of ortholog groups for individual protein-encoding genes across gene cluster instances. In addition, zol performs functional annotation and computes a variety of evolutionary statistics for each inferred ortholog group. Importantly, in comparison to tools for visual exploration of homologous relationships between gene clusters, zol can scale to thousands of gene cluster instances and produce detailed reports that are easy to digest. To showcase fai and zol, we apply them for: (i) longitudinal tracking of a virus in metagenomes, (ii) discovering novel population-level genetic insights of two common BGCs in the fungal species Aspergillus flavus, and (iii) uncovering large-scale evolutionary trends of a virulence-associated gene cluster across thousands of genomes from a diverse bacterial genus.

Exploring the Diversity and Specificity of Secondary Biosynthetic Potential in Rhodococcus.

The actinomycete genus Rhodococcus is known for its diverse biosynthetic enzymes, with potential in pollutant degradation, chemical biocatalysis, and natural product exploration. Comparative genomics have analyzed the distribution patterns of non-ribosomal peptide synthetases (NRPSs) in Rhodococcus. The diversity and specificity of its secondary metabolism offer valuable insights for exploring natural products, yet remain understudied. In the present study, we analyzed the distribution patterns of biosynthetic gene clusters (BGCs) in the most comprehensive Rhodococcus genome data to date. The results show that 86.5% of the gene cluster families (GCFs) are only distributed in a specific phylogenomic-clade of Rhodococcus, with the most predominant types of gene clusters being NRPS and ribosomally synthesized and post-translationally modified peptides (RiPPs). In-depth mining of RiPP gene clusters revealed that Rhodococcus encodes many clade-specific novel RiPPs, with thirteen core peptides showing antibacterial potential. High-throughput elicitor screening (HiTES) and non-targeted metabolomics revealed that a marine-derived Rhodococcus strain produces a large number of new aurachin-like compounds when exposed to specific elicitors. The present study highlights the diversity and specificity of secondary biosynthetic potential in Rhodococcus, and provides valuable information for the targeted exploration of novel natural products from Rhodococcus, especially for phylogenomic-clade-specific metabolites.

Full-length transcriptome analysis of Ophioglossum vulgatum: effects of experimentally identified chloroplast gene clusters on expression and evolutionary patterns.

Genes with similar or related functions in chloroplasts are often arranged in close proximity, forming clusters on chromosomes. These clusters are transcribed coordinated to facilitate the expression of genes with specific function. Our previous study revealed a significant negative correlation between the chloroplast gene expression level of the rare medicinal fern Ophioglossum vulgatum and its evolutionary rates as well as selection pressure. Therefore, in this study, we employed a combination of SMRT and Illumina sequencing technology to analyze the full-length transcriptome sequencing of O. vulgatum for the first time. In particular, we experimentally identified gene clusters based on transcriptome data and investigated the effects of chloroplast gene clustering on expression and evolutionary patterns. The results revealed that the total sequenced data volume of the full-length transcriptome of O. vulgatum amounted to 71,950,652,163bp, and 110 chloroplast genes received transcript coverage. Nine different types of gene clusters were experimentally identified in their transcripts. The chloroplast cluster genes may cause a decrease in non-synonymous substitution rate and selection pressure, as well as a reduction in transversion rate, transition rate, and their ratio. While expression levels of chloroplast cluster genes in leaf, sporangium, and stem would be relatively elevated. The Mann-Whitney U test indicated statistically significant in the selection pressure, sporangia and leaves groups (P < 0.05). We have contributed novel full-length transcriptome data resources for ferns, presenting new evidence on the effects of chloroplast gene clustering on expression land evolutionary patterns, and offering new theoretical support for transgenic research through gene clustering.

Genomic Insights into Combating Anthracnose with an Endophytic Bacillus amyloliquefaciens Strain.

Anthracnose, caused by Colletotrichum spp., is a common disease of Camellia oleifera. In this study, a Bacillus amyloliquefaciens strain, GZY63, was isolated from fruit of the anthracnose-resistant cultivar of Ca. oleifera "Ganzhouyou7." Plate confrontation assays and field experiments demonstrated the strong inhibitory effect of GZY63 on anthracnose, and this strain exhibited broad-spectrum resistance to nine pathogenic Colletotrichum spp. This strain shows potential as a fungicide alternative, but genetic information on this strain is critical for its optimal use. Combining Illumina and Nanopore sequencing, we assembled a high-quality circular genome of GZY63 that contained no plasmids. The GZY63 complete genome was approximately 3.93 Mb and had an average guanine-cytosine content of 46.5%. The genome comprised 4,024 predicted coding sequences and 12 types of gene clusters involved in secondary metabolite production. This genome information provides insights into the mechanism underlying the antagonistic impact of the GZY63 strain on anthracnose and its symbiotic relationship with Ca. oleifera.

Crystal structures of OrfX1, OrfX2 and the OrfX1-OrfX3 complex from the orfX gene cluster of botulinum neurotoxin E1.

Botulinum neurotoxins (BoNTs) are among the most lethal toxins known to humans, comprising seven established serotypes termed BoNT/A-G encoded in two types of gene clusters (ha and orfX) in BoNT-producing clostridia. The ha cluster encodes four non-toxic neurotoxin-associated proteins (NAPs) that assemble with BoNTs to protect and enhance their oral toxicity. However, the structure and function of the orfX-type NAPs remain largely unknown. Here, we report the crystal structures for OrfX1, OrfX2, and an OrfX1-OrfX3 complex, which are encoded in the orfX cluster of a BoNT/E1-producing Clostridium botulinum strain associated with human foodborne botulism. These structures lay the foundation for future studies on the potential roles of OrfX proteins in oral intoxication and pathogenesis of BoNTs.

4000 metres closer to novel antibiotics: a bioprospecting tale of three Streptomyces strains from the Andes

Bioprospecting of underexplored environments and microbiomes remains one of the core strategies for drug discovery. Páramos, a high-altitude ecosystem and evolutionary hotspot in the northern Andes of South America, harbour microbial diversity yet to be studied for its potential for antibiotic production. In this project, three strains (CG885, CG893 and CG926) isolated from a páramo in Colombia were explored using phylogenetic and genome mining tools to uncover their potential for novel antimicrobials. Taxonomic characterisation of three isolates suggested strains CG885 and CG893 can be classified as Streptomyces pratensis while strain CG926 is likely to be a new Streptomyces species. All three strains showed the biosynthetic coding capacity characteristic of streptomycetes and a diverse repertoire of biosynthetic gene cluster types likely to encode for novel specialised metabolites. One cluster in the strain CG926, for instance, is predicted to encode for a new halogenated compound containing the unusual nonproteinogenic amino acid piperazic acid with no known analogue. Integration of these results with phenotypic and metabolomic data will enable the assessment of these molecules and their antimicrobial activity. Overall, these results demonstrated that these three strains from an underexplored environment harbour the potential to become producers of novel antibiotics.

Dairy streptococcal cell wall and exopolysaccharide genome diversity.

The large-scale and high-intensity application of Streptococcus thermophilus species in milk fermentation processes is associated with a persistent threat of (bacterio)phage infection. Phage infection of starter cultures may cause inconsistent, slow or even failed fermentations with consequent diminished product quality and/or output. The phage life cycle commences with the recognition of, and binding to, a specific host-encoded and surface-exposed receptor, which in the case of S. thermophilus can be the rhamnose-glucose polysaccharide (RGP; specified by the rgp gene cluster) or exopolysaccharide (EPS; specified by the eps gene cluster). The genomic diversity of 23 S . thermophilus strains isolated from unpasteurized dairy products was evaluated, including a detailed analysis of the rgp and eps loci. In the present study, five novel eps genotypes were identified while variations of currently recognized rgp gene cluster types were also observed. Furthermore, the diversity of rgp genotypes amongst retrieved isolates positively correlated with phage diversity based on phageome analysis of eight representative dairy products. Our findings therefore substantially expand our knowledge on S. thermophilus’ strain and phage diversity in (artisanal) dairy products and highlight the merit of phageome analysis of artisanal and traditional fermented foods as a sensitive marker of dominant microbiota involved in the fermentation.

Characterization of the O-antigen gene clusters and development of a molecular serotyping method for Vibrio fluvialis

Vibrio fluvialis is an emerging foodborne pathogen that causes severe infections. Serotyping based on surface polysaccharide antigens is important for the clinical detection and epidemiological surveillance of pathogens such as V. fluvialis. For example, variation of the O-antigen, which is highly polymorphic and is responsible for the majority of antigenic variability on the bacterial cell surface, provides the basis for serotyping of Gram-negative bacteria. Currently, there has been no analysis of the O-antigen gene clusters in V. fluvialis. In this study, the putative O-antigen gene clusters of 18 V. fluvialis serogroups (O1–O18), which exhibit a high level diversity, were analyzed by whole-genome sequencing. A microsphere-based suspension array (MSA) based on O-serogroup-specific genes was developed for identification of V. fluvialis strains O1–O18 and evaluated for specificity and sensitivity in double-blind tests. Furthermore, analysis of 62 publicly available V. fluvialis genomes identified 13 new O-antigen gene cluster types. The detection sensitivity was determined to be 10−2 ng for genomic DNA and 103 CFU for pure cultures. When testing simulated samples in an oyster background, 2 to 20 CFU per gram inoculated could be detected after enrichment using this method. Our work provides an efficient tool for rapid detection and identification of V. fluvialis serogroups from clinical and environmental samples, with the potential for use in epidemiological investigations and food safety applications.

Discovery and Characterization of Rubrinodin Provide Clues into the Evolution of Lasso Peptides.

Lasso peptides are unique natural products that comprise a class of ribosomally synthesized and post-translationally modified peptides. Their defining three-dimensional structure is a lariat knot, in which the C-terminal tail is threaded through a macrolactam ring formed between the N-terminal amino group and an Asp or Glu side chain (i.e., an isopeptide bond). Recent genome mining strategies have revealed various types of lasso peptide biosynthetic gene clusters and have thus redefined the known chemical space of lasso peptides. To date, over 20 different types of these gene clusters have been discovered, including several different clades from Proteobacteria. Despite the diverse architectures of these gene clusters, which may or may not encode various tailoring enzymes, most currently known lasso peptides are synthesized by two discrete clades defined by the presence of an ATP-binding cassette transporter or its absence and (sometimes) concurrent appearance of an isopeptidase, raising questions about their evolutionary history. Herein, we discovered and characterized the lasso peptide rubrinodin, which is assembled by a gene cluster encoding both an ATP-binding cassette transporter and an isopeptidase. Our bioinformatics analyses of this and other representative cluster types provided new clues into the evolutionary history of lasso peptides. Furthermore, our structural and biochemical investigations of rubrinodin permitted the conversion of this thermolabile lasso peptide into a more thermostable scaffold.

Complete Genome Resource of Bacillus velezensis J17-4, an Endophyte Isolated from Stem Tissues of Rice.

Dickeya zeae is the causative agent of rice root rot disease and causes severe harvest and economic losses. In this study, the Bacillus velezensis strain J17-4 with significant antagonism against D. zeae was used to generate DNA for sequencing. After assembly, a high-quality complete genome comprising only a circular chromosome was available. The genome sequence consists of a total of 3,877 prediction coding sequences and nine types of gene clusters involved in secondary metabolite production. This genome data will provide information for understanding the underlying mechanism of strain J17-4 antagonist against D. zeae and a new useful source for comparative genomics studies between strains isolated from various habitats.

The Distinctive Evolution of orfX Clostridium parabotulinum Strains and Their Botulinum Neurotoxin Type A and F Gene Clusters Is Influenced by Environmental Factors and Gene Interactions via Mobile Genetic Elements.

Of the seven currently known botulinum neurotoxin-producing species of Clostridium, C. parabotulinum, or C. botulinum Group I, is the species associated with the majority of human botulism cases worldwide. Phylogenetic analysis of these bacteria reveals a diverse species with multiple genomic clades. The neurotoxins they produce are also diverse, with over 20 subtypes currently represented. The existence of different bont genes within very similar genomes and of the same bont genes/gene clusters within different bacterial variants/species indicates that they have evolved independently. The neurotoxin genes are associated with one of two toxin gene cluster types containing either hemagglutinin (ha) genes or orfX genes. These genes may be located within the chromosome or extrachromosomal elements such as large plasmids. Although BoNT-producing C parabotulinum bacteria are distributed globally, they are more ubiquitous in certain specific geographic regions. Notably, northern hemisphere strains primarily contain ha gene clusters while southern hemisphere strains have a preponderance of orfX gene clusters. OrfX C. parabotulinum strains constitute a subset of this species that contain highly conserved bont gene clusters having a diverse range of bont genes. While much has been written about strains with ha gene clusters, less attention has been devoted to those with orfX gene clusters. The recent sequencing of 28 orfX C. parabotulinum strains and the availability of an additional 91 strains for analysis provides an opportunity to compare genomic relationships and identify unique toxin gene cluster characteristics and locations within this species subset in depth. The mechanisms behind the independent processes of bacteria evolution and generation of toxin diversity are explored through the examination of bacterial relationships relating to source locations and evidence of horizontal transfer of genetic material among different bacterial variants, particularly concerning bont gene clusters. Analysis of the content and locations of the bont gene clusters offers insights into common mechanisms of genetic transfer, chromosomal integration, and development of diversity among these genes.

Two new types of triploid hybrids derived from Cyprinus carpio (♀) × Megalobrama amblycephala (♂)

Based on the formation of an autotetraploid fish lineage (4nNC, 4n = 200, F1-F4) derived from common carp (Cyprinus carpio, 2nCOC, 2n = 100) (♀) × blunt snout bream (Megalobrama amblycephala, 2nBSB, 2n = 48) (♂), we produced two new types of triploid hybrids. One type of triploid hybrid (3nNCRC) was produced by crossing females of a crucian carp-like homodiploid fish (2nNCRC, 2n = 100) with males of 4nNC; the other type of triploid hybrid (3nMCC) was generated by crossing females of an improved diploid scattered mirror carp (2nIDMC) with males of 4nNC. The 2nNCRC and 2nIDMC were derived from the first generation of 2nCOC (♀) × 2nBSB (♂). In this study, we comparatively investigated the morphological traits, chromosomal numbers, DNA contents, erythrocyte traits, and DNA variations in 5S rDNA and Hox genes in 3nNCRC and 3nMCC. The results at the chromosome and DNA content levels indicated that 3nNCRC and 3nMCC had 150 chromosomes originating from common carp and were triploid hybrids. The proportion of erythrocytes with a dumbbell-shaped nucleus in 3nNCRC (1.74 ± 0.44%) was not significantly different (P > .05) from that in 3nMCC (2.86 ± 0.59%). Regarding the cluster organization of six Hox genes, 3nNCRC and 3nMCC had greater genetic variations; they not only inherited some Hox gene cluster types (including partial recombinant clusters) from each of the parents but also presented some new gene cluster types (including a richer variety of recombinant clusters) or lost some gene cluster types, suggesting a clear source of hybridization for 3nNCRC and 3nMCC and instability in the newly established triploid hybrid genomes. Moreover, 3nNCRC and 3nMCC had derived the same type of HoxB5b gene cluster, or some derived gene clusters from one fish were identical to those of the other fish with the same gene clusters inherited from their parents. Meanwhile, compared with 3nMCC, 3nNCRC exhibited greater variation in 5S rDNA and Hox gene structures, which revealed that the genome composition of 3nNCRC was more complex and less stable. The successful development of these two new types of triploid hybrids is of great significance for fish genetic breeding.

Characterization of l-2-keto-3-deoxyfuconate aldolases in a nonphosphorylating l-fucose metabolism pathway in anaerobic bacteria

Characterization of l-2-keto-3-deoxyfuconate aldolases in a nonphosphorylating l-fucose metabolism pathway in anaerobic bacteria

Genome-resolved metagenomics identifies genetic mobility, metabolic interactions, and unexpected diversity in perchlorate-reducing communities.

Dissimilatory perchlorate reduction is an anaerobic respiratory pathway that in communities might be influenced by metabolic interactions. Because the genes for perchlorate reduction are horizontally transferred, previous studies have been unable to identify uncultivated perchlorate-reducing populations. Here we recovered metagenome-assembled genomes from perchlorate-reducing sediment enrichments and employed a manual scaffolding approach to reconstruct gene clusters for perchlorate reduction found within mobile genetic elements. De novo assembly and binning of four enriched communities yielded 48 total draft genomes. In addition to canonical perchlorate reduction gene clusters and taxa, a new type of gene cluster with an alternative perchlorate reductase was identified. Phylogenetic analysis indicated past exchange between these gene clusters, and the presence of plasmids with either gene cluster shows that the potential for gene transfer via plasmid persisted throughout enrichment. However, a majority of genomes in each community lacked perchlorate reduction genes. Putative chlorate-reducing or sulfur-reducing populations were dominant in most communities, supporting the hypothesis that metabolic interactions might result from perchlorate reduction intermediates and byproducts. Other populations included a novel phylum-level lineage (Ca. Muirbacteria) and epibiotic prokaryotes with no known role in perchlorate reduction. These results reveal unexpected genetic diversity, suggest that perchlorate-reducing communities involve substantial metabolic interactions, and encourage expanded strategies to further understand the evolution and ecology of this metabolism.

Diversity of mitochondrial plastid DNAs (MTPTs) in seed plants

Mitochondrial plastid DNAs (MTPTs) refer to plastid-derived DNA fragments in mitochondrial genomes. While the MTPTs have been described for numerous species, its overall patterns have not been examined in details. Here, we carried out a systematic analysis of MTPTs among 73 plant species, including 28 algae, 1 liverwort, 2 moss, 1 lycophyte, 1 gymnosperm, 1 magnoliid, 12 monocots, 26 eudicots and 1 relic angiosperm Amborella trichopoda. A total of 300 MTPT gene clusters were found in 39 seed plants, which represented 144 MTPT gene cluster types. The detected MTPT gene clusters were evaluated in seven aspects, and they were found to be enriched particularly in monocots and asterids of eudicots. Some MTPT gene clusters were found to be shared by closely related species. All chloroplast genes were found in MTPTs, suggesting that there is no functional relevancy for genes that were transferred. However, after calculation of the frequency of the 115 chloroplast genes, five hot spots and three cold spots were discovered in chloroplast genome. In summary, this study demonstrated the high degree of diversity in MTPTs. The discovered MTPTs would facilitate the accurate assembly of chloroplast and mitochondrial genomes as well as the understanding of organelle genome evolution.

The PhytoClust tool for metabolic gene clusters discovery in plant genomes.

The existence of Metabolic Gene Clusters (MGCs) in plant genomes has recently raised increased interest. Thus far, MGCs were commonly identified for pathways of specialized metabolism, mostly those associated with terpene type products. For efficient identification of novel MGCs, computational approaches are essential. Here, we present PhytoClust; a tool for the detection of candidate MGCs in plant genomes. The algorithm employs a collection of enzyme families related to plant specialized metabolism, translated into hidden Markov models, to mine given genome sequences for physically co-localized metabolic enzymes. Our tool accurately identifies previously characterized plant MGCs. An exhaustive search of 31 plant genomes detected 1232 and 5531 putative gene cluster types and candidates, respectively. Clustering analysis of putative MGCs types by species reflected plant taxonomy. Furthermore, enrichment analysis revealed taxa- and species-specific enrichment of certain enzyme families in MGCs. When operating through our web-interface, PhytoClust users can mine a genome either based on a list of known cluster types or by defining new cluster rules. Moreover, for selected plant species, the output can be complemented by co-expression analysis. Altogether, we envisage PhytoClust to enhance novel MGCs discovery which will in turn impact the exploration of plant metabolism.

Natural Product Proteomining, a Quantitative Proteomics Platform, Allows Rapid Discovery of Biosynthetic Gene Clusters for Different Classes of Natural Products

Information on gene clusters for natural product biosynthesis is accumulating rapidly because of thecurrent boom of available genome sequencing data. However, linking a natural product to a specific gene cluster remains challenging. Here, we present a widely applicable strategy for the identification of gene clusters for specific natural products, which we name natural product proteomining. The method is based on using fluctuating growth conditions that ensure differential biosynthesis of the bioactivity of interest. Subsequent combination of metabolomics and quantitative proteomics establishes correlations between abundance of natural products and concomitant changes in the protein pool, which allows identification of the relevant biosynthetic gene cluster. We used this approach to elucidate gene clusters for different natural products in Bacillus and Streptomyces, including a novel juglomycin-type antibiotic. Natural product proteomining does not require prior knowledge of the gene cluster or secondary metabolite and therefore represents a general strategy for identification of all types of gene clusters.

Nitro versus Hydroxamate in Siderophores of Pathogenic Bacteria: Effect of Missing Hydroxylamine Protection in Malleobactin Biosynthesis

Siderophores play a major role as virulence factors of pathogenic bacteria. Known as the strongest Fe-binding agents, these structurally diverse compounds are used to scavenge scarcely soluble iron from the human or animal hosts. Strikingly, infamous human pathogenic bacteria like Yersinia pestis, the causative agent of devastating black death epidemics, completely lose their virulence in the absence of a siderophore. Thus, knowledge of a pathogen s siderophore structures and of the corresponding biosynthetic machineries is considered a prerequisite for new therapeutic approaches such as targeting pathogenicity factors and Trojan horse strategies using siderophore–drug conjugates. Over the past two decades, much research has been devoted to elucidating the siderophores of Burkholderia mallei and Burkholderia pseudomallei, the causative agents of the infectious diseases glanders and melioidosis. Infections with these b-proteobacteria are often lethal, even with the best treatment available. Both species have thus been categorized as potential biological warfare agents, and indeed B. mallei has been abused in World War I to kill enemy horses and mules. Although it has long been known that B. pseudomallei and B. mallei produce two types of siderophores, pyochelin (1 and 2’’-epi-1, Figure 1) and malleobactin (2), surprisingly, the structure of the latter has remained obscure. It was only a matter of speculation that malleobactin could be related to the ornibactins (3–5, Scheme 1), hydroxamate siderophores produced by the Burkholderia cepacia complex (Bcc). Here we disclose the unusual structure and absolute configuration of malleobactin, the siderophore of the human pathogenic B. mallei family and reveal the biogenetic origin of an unprecedented aliphatic nitro amino acid. To gain first insights into the structural deviations of the encoded siderophores, we compared the gene loci for ornibactin and malleobactin biosynthesis. Both types of gene clusters share genes for a tetramodular nonribosomal peptide synthetase (NRPS) and accessory enzymes. Furthermore, genes for putative amino acid tailoring enzymes (ornithine monooxygenase, aspartic acid b-hydroxylase, N-formyltransferase), siderophore receptors and transporters are present in both types of gene clusters. However, we noted that the gene loci in bacteria belonging to the B. mallei family harbor an additional gene for a hypothetical protein (mbaM), but lack orthologues of orbK and orbL (Figure 1A, yellow open reading frames (orfs)). The latter genes code for acyltransferases, and although their biochemical function has not yet been studied, one may assume that they are required for loading acyl units onto the N-terminal ornithine residue. We concluded that ornibactins and malleobactin differ in their substitution patterns. Figure 1. Comparison of malleobactin and ornibactin biosynthesis gene clusters (mba and orb, respectively) of Burkholderia spp., and analysis of siderophore production of B. thailandensis. A) Malleobactin biosynthesis gene clusters: Bm : B. mallei ; Bp : B. pseudomallei ; Bt : B. thailandensis. Ornibactin biosynthesis gene clusters: Bc : B. cenocepacia ; Ba : B. ambifaria. Deduced functions of mba biosynthesis genes, see Table S2 in the Supporting Information. pvd genes refer to orthologues from the pyoverdin biosynthesis gene cluster in Pseudomonas spp. B) CAS agar plate assay of B. thailandensis wild type (a), DpchE mutant (b, pch=pyochelin biosynthesis gene cluster), DmbaA mutant (c), DpchEDmbaA mutant (d). C) LC–MS profiles monitoring malleobactin (2, m/z 637) and pyochelin (1 and 2’’-epi-1, m/z 325) production of mutant strains (as in (B)).

Genomics of schizophrenia and pharmacogenomics of antipsychotic drugs

Antipsychotic drugs are the neuroleptics currently used in the treatment of schizophrenia (SCZ) and psychotic disorders. SCZ has a heritability estimated at 70% - 90%; and pharmacogenomics accounts for 60% - 90% variability in the pharmacokinetics and pharmacodynamics of psychotropic drugs. Personalized therapeutics based on individual genomic profiles in SCZ entails the characterization of 5 types of gene clusters and their related metabolomic profiles: 1) genes associated with disease pathogenesis; 2) genes associated with the mechanism of action of drugs; 3) genes associated with drug metabolism (phase I and II reactions); 4) genes associated with drug transporters; and 5) pleiotropic genes involved in multifaceted cascades and metabolic reactions. Genetic studies in SCZ have revealed the presence of chromosome anomalies, copy number variants, multiple single-nucleotide polymorphisms of susceptibility distributed across the human genome, aberrant single-nucleotide polymorphisms in microRNA genes, mitochondrial DNA mutations, and epigenetic phenomena. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variation in specific candidate genes and the positive and adverse effects of drug treatment. Approximately 18% of neuroleptics are major substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4. About 10% - 20% of Western populations are defective in genes of the CYP superfamily. Only 26% of Southern Europeans are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6 + CYP2C19 + CYP2C9 genes. Efficacy and safety issues in the pharmacological treatment of SCZ are directly linked to genetic clusters involved in the pharmacogenomics of antipsychotic drugs and also to environmental factors. Consequently, the incorporation of pharmacogenomic procedures both to drugs under development and drugs on the market would help to optimize therapeutics in SCZ and other central nervous system disorders.

Widespread occurrence of secondary lipid biosynthesis potential in microbial lineages.

Bacterial production of long-chain omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), is constrained to a narrow subset of marine γ-proteobacteria. The genes responsible for de novo bacterial PUFA biosynthesis, designated pfaEABCD, encode large, multi-domain protein complexes akin to type I iterative fatty acid and polyketide synthases, herein referred to as “Pfa synthases”. In addition to the archetypal Pfa synthase gene products from marine bacteria, we have identified homologous type I FAS/PKS gene clusters in diverse microbial lineages spanning 45 genera representing 10 phyla, presumed to be involved in long-chain fatty acid biosynthesis. In total, 20 distinct types of gene clusters were identified. Collectively, we propose the designation of “secondary lipids” to describe these biosynthetic pathways and products, a proposition consistent with the “secondary metabolite” vernacular. Phylogenomic analysis reveals a high degree of functional conservation within distinct biosynthetic pathways. Incongruence between secondary lipid synthase functional clades and taxonomic group membership combined with the lack of orthologous gene clusters in closely related strains suggests horizontal gene transfer has contributed to the dissemination of specialized lipid biosynthetic activities across disparate microbial lineages.