Biology subjects

Weinstock, G. M.

Publications and source records attributed to Weinstock, G. M..

7 recordsLinked to original sources

bioRxiv2024

Longitudinal profiling of the microbiome at four body sites reveals core stability and individualized dynamics during health and disease

To understand dynamic interplay between the human microbiome and host during health and disease, we analyzed the microbial composition, temporal dynamics, and associations with host multi-omics, immune and clinical markers of microbiomes from four body sites in 86 participants over six years. We found that microbiome stability and individuality are body-site-specific and heavily influenced by the host. The stool and oral microbiome were more stable than the skin and nasal microbiomes, possibly due to their interaction with the host and environment. Also, we identified individual-specific and commonly shared bacterial taxa, with individualized taxa showing greater stability. Interestingly, microbiome dynamics correlated across body sites, suggesting systemic coordination influenced by host-microbial-environment interactions. Notably, insulin-resistant individuals showed altered microbial stability and associations between microbiome, molecular markers, and clinical features, suggesting their disrupted interaction in metabolic disease. Our study offers comprehensive views of multi-site microbial dynamics and their relationship with host health and disease. Study HighlightsO_LIThe stability of the human microbiome varies among individuals and body sites. C_LIO_LIHighly individualized microbial genera are more stable over time. C_LIO_LIAt each of the four body sites, systematic interactions between the environment, the host and bacteria can be detected. C_LIO_LIIndividuals with insulin resistance have lower microbiome stability, a more diversified skin microbiome, and significantly altered host-microbiome interactions. C_LI

microbiology↗

bioRxiv2022

Microbial glutamate metabolism predicts intravenous cocaine self-administration in Diversity Outbred mice

The gut microbiome is thought to play a critical role in the onset and development of psychiatric disorders, including depression and substance use disorder (SUD). To test the hypothesis that the microbiome affects addiction predisposing behaviors and cocaine intravenous self-administration (IVSA) and to identify specific microbes involved in the relationship, we performed 16S rRNA gene sequencing on feces from 228 diversity outbred mice. Twelve open field measures, two light-dark assay measures, one hole board and novelty place preference measure significantly differed between mice that acquired cocaine IVSA (ACQ) and those that failed to acquire IVSA (FACQ). We found that ACQ mice are more active and exploratory and display decreased fear than FACQ mice. The microbial abundances that differentiated ACQ from FACQ mice were an increased abundance of Barnesiella, Ruminococcus, and Robinsoniella and decreased Clostridium IV in ACQ mice. There was a sex-specific correlation between ACQ and microbial abundance, a reduced Lactobacillus abundance in ACQ male mice, and a decreased Blautia abundance in female ACQ mice. The abundance of Robinsoniella was correlated, and Clostridium IV inversely correlated with the number of doses of cocaine self-administered during acquisition. Functional analysis of the microbiome composition of a subset of mice suggested that gut-brain modules encoding glutamate metabolism genes are associated with the propensity to self-administer cocaine. These findings establish associations between the microbiome composition and glutamate metabolic potential and the ability to acquire cocaine IVSA thus indicating the potential translational impact of targeting the gut microbiome or microbial metabolites for treatment of SUD. HIGHLIGHTSO_LICorrelational analysis of novelty behaviors to IVSA acquisition shows that mice that acquire cocaine IVSA are more active and exploratory and have decreased fear than those that failed-to-acquire IVSA. C_LIO_LIThe gut microbiome profiling of 228 diversity outbred mice indicates the relative abundances of Barnesiella, Ruminococcus, Robinsoniella and Clostridium IV are associated with the ability to self-administer cocaine. C_LIO_LIAssociations between the gut microbiome and IVSA acquisition are sex-specific. Decreased relative abundances of Lactobacillus and Blautia are associated with IVSA in male and female mice, respectively. C_LIO_LIThe relative abundances of Robinsoniella and Clostridium IV were correlated with the number of infusions of self-administered cocaine. C_LIO_LIFunctional potential analysis of the gut microbiome supports a role for microbiomes encoding glutamate metabolism in the ability to self-administer cocaine. C_LI

neuroscience↗

bioRxiv2019

SVants: A long-read based method for structural variation detection in bacterial genomes

MotivationMobile genetic elements (MGEs) are genetic material that can transfer between bacterial cells and move to new locations within a single bacterial genome. These elements range from several hundred to tens of thousands of bases, and are often bordered by repeat regions, which makes resolving these elements difficult with short-read sequencing data. The development and availability of long-read sequencing technologies has opened up new opportunities in the study of structural variation but there is a lack of bioinformatics tools designed to take advantage of these longer reads.\n\nResultsWe present an assembly-free method for identifying the location of these MGEs when compared to any reference genome (including draft genomes). Using an artificially constructed Escherichia coli genome containing single and tandem-repeats of a Tn9 transposon, we demonstrate the ability of SVants to accurately identify multiple insertion sites as well as count the number of repeats of this MGE. Additionally, we show that SVants accurately identifies the transposon of interest, Tn9, but does not erroneously identify existing IS1 regions present within the chromosome of the E. coli artificial reference.\n\nAvailability and ImplementationSVants is available as open-source software at https://github.com/EpiBlake/SVants

bioinformatics↗

bioRxiv2019

Characterization of Mucosal Dysbiosis of Early Colonic Neoplasia

Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesion in the colon that can be detected by high-definition chromoendoscopy with contrast dye-spray. Although frequently associated with synchronous adenomas, their role in colorectal tumor development, particularly in the proximal colon, is still not clear. The goal of this study was to evaluate the profile of colon-associated bacteria associated with proximal ACF and to investigate their relationship to the presence and subtype of synchronous polyps present throughout the colon. Forty-five subjects undergoing a screening or surveillance colonoscopy were included in this retrospective study. Our study cohort included a total of 16 subjects with no identifiable proximal lesions (either ACF or polyp), 14 subjects with at least 1 ACF but no polyp(s), and 15 subjects with both at least 1 ACF and a synchronous proximal polyp(s) detected at colonoscopy. Bacterial cells adherent to the epithelia of ACF and normal mucosa were visualized by in situ hybridization within confocal sections. Bacterial DNA isolated from biopsies was used to construct PCR amplicon libraries targeting the V4 hypervariable region of the 16S rRNA gene, which were then sequenced on the Illumina platform. ACF showed significantly greater heterogeneity in their bacterial profiles compared to normal mucosa. Interestingly, one of the bacterial community structures we characterized was strongly correlated with the presence of synchronous polyps. The observed dysbiosis is more prominent within the colonic epithelium that also harbors synchronous polyps. Finally using DNA-mass spectrometry to evaluate a panel of colorectal cancer hot-spot mutations present in the ACF, we found that several APC gene mutations (R1450*, R876*, S1465fs*3) were positively associated with the presence of Instestinibacter sp., whereas KRAS mutations (G12V, G12D) were positively correlated with Ruminococcus gnavus. This result indicates a potential relationship between specific colon-associated bacterial species and somatically acquired CRC-related mutations. Overall, our findings suggest that perturbations to the normal adherent mucosal flora may constitute a risk factor for early neoplasia, demonstrating the potential impact of mucosal dysbiosis on the tissue microenvironment and behavior of ACF that may facilitate (or impede) their progression towards more advanced forms of neoplasia.

microbiology↗

bioRxiv2019

Biogeography and Microscale Diversity Shape the Biosynthetic Potential of Fungus-growing Ant-associated Pseudonocardia

The geographic and phylogenetic scale of ecologically relevant microbial diversity is still poorly understood. Using a model mutualism, fungus-growing ants and their defensive bacterial associate Pseudonocardia, we analyzed genetic diversity and biosynthetic potential in 46 strains isolated from ant colonies in a 20km transect near Barro Colorado Island in Panama. Despite an average pairwise core genome similarity of greater than 99%, population genomic analysis revealed several distinct bacterial populations matching ant host geographic distribution. We identified both genetic diversity signatures and divergent genes distinct to each lineage. We also identify natural product biosynthesis clusters specific to isolation locations. These geographic patterns were observable despite the populations living in close proximity to each other and provides evidence of ongoing genetic exchange. Our results add to the growing body of literature suggesting that variation in traits of interest can be found at extremely fine phylogenetic scales.

microbiology↗

bioRxiv2019

The genome of C57BL/6J \"Eve\", the mother of the laboratory mouse genome reference strain

Isogenic laboratory mouse strains are used to enhance reproducibility as individuals within a strain are essentially genetically identical. For the most widely used isogenic strain, C57BL/6, there is also a wealth of genetic, phenotypic, and genomic data, including one of the highest quality reference genomes (GRCm38.p6). However, laboratory mouse strains are living reagents and hence genetic drift occurs and is an unavoidable source of accumulating genetic variability that can have an impact on reproducibility over time. Nearly 20 years after the first release of the mouse reference genome, individuals from the strain it represents (C57BL/6J) are at least 26 inbreeding generations removed from the individuals used to generate the mouse reference genome. Moreover, C57BL/6J is now maintained through the periodic reintroduction of mice from cryopreserved embryo stocks that are derived from a single breeder pair, aptly named C57BL/6J Adam and Eve. To more accurately represent the genome of todays C57BL/6J mice, we have generated a de novo assembly of the C57BL/6J Eve genome (B6Eve) using high coverage, long-read sequencing, optical mapping, and short-read data. Using these data, we addressed recurring variants observed in previous mouse studies. We have also identified structural variations that impact coding sequences, closed gaps in the mouse reference assembly, some of which are in genes, and we have identified previously unannotated coding sequences through long read sequencing of cDNAs. This B6Eve assembly explains discrepant observations that have been associated with GRCm38-based analyses, and has provided data towards a reference genome that is more representative of the C57BL/6J mice that are in use today.

genomics↗

bioRxiv2016

Genetic variation and gene expression across multiple tissues and developmental stages in a non-human primate

By analyzing multi-tissue gene expression and genome-wide genetic variation data in samples from a vervet monkey pedigree, we generated a transcriptome resource and produced the first catalogue of expression quantitative trait loci (eQTLs) in a non-human primate model. This catalogue contains more genome-wide significant eQTLs, per sample, than comparable human resources, and reveals sex and age-related expression patterns. Findings include a master regulatory locus that likely plays a role in immune function, and a locus regulating hippocampal long non-coding RNAs (lncRNAs), whose expression correlates with hippocampal volume. This resource will facilitate genetic investigation of quantitative traits, including brain and behavioral phenotypes relevant to neuropsychiatric disorders.

genetics↗