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Influence of multi-species data on gene-disease associations in substance use disorder using random walk with restart models.
Get PDFA major challenge lies in discovering, emphasizing, and characterizing human gene-disease and gene-gene associations. The limitations of data on the role of human gene products in substance use disorder (SUD) makes it challenging to transition from genetic associations to actionable insights. The integration of data from multiple diverse sources, including information-dense studies in model organisms, has the potential to address this gap. We demonstrate a modified performance of the Random Walk with Restart algorithm when multi-species data is integrated in the heterogeneous network within the context of SUD. Additionally, our approach distinguishes among disparate pathways derived from the Kyoto Encyclopedia of Genes and Genomes. Thus, we conclude that direct incorporation of multi-species data to an aggregated heterogeneous knowledge graph can adjust RWR\u27s performance and enables users to discover new gene-disease and gene-gene associations
Survivorship from pediatric and adult brain tumors: The 2024 Brain Tumor Epidemiology Consortium meeting report.
Get PDFThe Brain Tumor Epidemiology Consortium (BTEC) is an international organization with membership of individuals from the scientific community with interests related to brain tumor epidemiology, including surveillance, classification, methodology, etiology, and factors associated with morbidity and survival. The 2024 annual BTEC meeting entitle
A Concordance Study among 26 NGS Laboratories Participating in the NCI Molecular Analysis for Therapy Choice Clinical Trial.
No full textPURPOSE: NCI selected a network of Clinical Laboratory Improvement Amendments-certified laboratories performing routine next-generation sequencing (NGS) tumor testing to identify patients for the NCI Molecular Analysis for Therapy Choice (NCI-MATCH) trial. This large network provided a unique opportunity to compare variant detection and reporting between a wide range of testing platforms.
EXPERIMENTAL DESIGN: Twenty-eight NGS assays from 26 laboratories within the NCI-MATCH Network, including the NCI-MATCH central laboratory (CL) and 11 commercial and 14 academic designated laboratories (DL), were used for this study. DNA from eight cell lines and two clinical samples were sequenced. Pairwise comparisons in variant detection and reporting between each DL and CL were performed for single-nucleotide variant, insertion and deletion, and copy-number variant classes.
RESULTS: We observed high concordance in variant detection between CL and DL for single-nucleotide variants and insertions and deletions [average positive agreement (APA) \u3e 95.4% for all pairwise comparisons] but lower concordance for variant reporting after analysis pipeline filtering. We observed much higher agreement between CL and assays using amplification as the target enrichment method (84.2% \u3c APA ≤ 95.7%, average APA = 88.7%) than other assays using hybridization capture (69.7% \u3c APA ≤ 93.8%, average APA = 77.4%) due to blacklisting of actionable variants in low complexity regions. For copy-number variant reporting, we observed high agreement (APA \u3e 82%) except between CL and two assays (APA = 76.9% and 71.4%) due to differences in estimation of copy numbers. Notably, for all variants, differences in variant interpretation also contributed to reporting discrepancies.
CONCLUSIONS: This study indicates that different NGS tumor profiling tests currently in widespread clinical use achieve high concordance between assays in variant detection. For variant reporting, observed discrepancies are mainly introduced during the bioinformatic analysis
Assessing Phasing Accuracy for Inferring Haplotype Structure in Laboratory Marmosets
No full textTo understand the genetics behind aging and complex diseases like Alzheimer’s, we need accurate ways to model how DNA varies between individuals. While studying genetic changes at singular positions (SNPs) is common, looking at haplotypes gives a deeper understanding of how genetic traits are inherited and organized. The common marmoset (Callithrix jacchus) is a useful model for studying these diseases due to similarities with humans, but broader genomic architecture including haplotype structure hasn’t been previously studied for this non-human primate species. In this project, we tested two phasing tools, Beagle and WhatsHap, to see which one more accurately identifies haplotypes from short-read whole-genome sequencing data. We used a high-confidence “truth set” created with WhatsHap, which incorporates pedigree structure (sequenced trios) with a read-backed algorithm to resolve haplotypes. We then compared this to two test sets: one phased with Beagle, which uses population-based statistical modeling through Hidden Markov Models (HMMs), and the other with WhatsHap without including any pedigree information. without including any pedigree information. WhatsHap with trio input performed best across all accuracy measures, including metrics like switch error rate, switch/flip rate and Hamming distance. Visual analysis with IGV showed that pedigree-based phasing better matched regions of strong linkage disequilibrium. Finally, we found that marmosets show LD decay patterns similar to humans, further supporting their value as a model for studying genetically complex traits. These results highlight the importance of using family data when phasing genomes in non-human primates and provide a strong foundation for future genetic studies in marmosets
Dissecting Keratinocyte Responses to Commensal and Pathogenic Staphylococcus Species Using a 3D Human Skin Model
No full textStaphylococcus aureus and Staphylococcus epidermidis are two common members of the skin microbiome. While S. aureus infection is associated with inflammatory skin disease and severe infection, and S. epidermidis is generally considered a commensal organism, little is known about how human skin cells distinguish between these species of contrasting pathogenic potential. Here, we use 3D skin models consisting of a layer of stratified keratinocytes grown on top of a fibroblast-embedded collagen matrix to show that barrier function-associated genes are differentially expressed upon stimulation with S. epidermidis versus S. aureus, as are two aryl-hydrocarbon receptor target genes, CYP1A1 and OVOL1. We also show that IL-1a expression and secretion is elevated upon stimulation with S. epidermidis, but not S. aureus. Overall, we provide preliminary evidence to suggest that host skin cells may differentially activate the proinflammatory response, increase the expression of proliferative keratin genes, and AhR target genes to distinguish between these two species
CRISPR/Cas13d Screen Identifies the Long Non-Coding RNA GAS5 as a Vulnerability in AML
No full textAcute myeloid leukemia (AML) is a heterogenous blood cancer characterized by the accumulation of myeloblasts, immature white blood cells. Unlike many solid tumors, AML typically harbors fewer genetic mutations on average and exhibits a high rate of relapse with few additional mutations being found. This suggests that non-genetic mechanisms play a critical role in AML pathogenesis. One such non-genetic mechanism is the participation of long non-coding RNAs (lncRNAs) which recently have been recognized to play a role in cancer development. To systematically uncover lncRNAs essential for AML survival and proliferation, we have conducted an extensive CRISPR/Cas13d RNA-targeting screen of over 7,000 annotated human lncRNAs. Among the top-scoring lncRNAs identified in our screen was GAS5, for which our preliminary data demonstrated a critical role in supporting AML cell proliferation
Comparison of Lysis and Amplification Methodologies for Optimal 16S rRNA Gene Profiling for Human and Mouse Microbiome Studies.
Get PDFWhen conducting sequence-based analysis of microbiome samples, it is important to accurately represent the bacterial communities present. The aim of this study was to compare two commercially available DNA isolation and PCR amplification approaches to determine their impact on the taxonomic composition of microbiome samples following 16S rRNA gene sequencing. A well-established 16S rRNA gene profiling approach, which was widely used in the Human Microbiome Project (HMP), was compared with a novel alkaline degenerative technique that utilizes alkaline cell lysis in combination with a degenerate pool of primers for nucleic acid extraction and PCR amplification. When comparing these different approaches for the microbiome profiling of human and mouse fecal samples, we found that the alkaline-based method was able to detect greater taxonomic diversity. An in silico analysis of predicted primer binding against a curated 16S rRNA gene reference database further suggested that this novel approach had the potential to reduce population bias found with traditional methods, thereby offering opportunities for improved microbial community profiling
Muscle-derived myostatin is a major endocrine driver of follicle-stimulating hormone synthesis.
No full textMyostatin is a paracrine myokine that regulates muscle mass in a variety of species, including humans. In this work, we report a functional role for myostatin as an endocrine hormone that directly promotes pituitary follicle-stimulating hormone (FSH) synthesis and thereby ovarian function in mice. Previously, this FSH-stimulating role was attributed to other members of the transforming growth factor-β family, the activins. Our results both challenge activin\u27s eponymous role in FSH synthesis and establish an unexpected endocrine axis between skeletal muscle and the pituitary gland. Our data also suggest that efforts to antagonize myostatin to increase muscle mass may have unintended consequences on fertility
The metabolic basis of cancer-related fatigue.
No full textAlthough we are all familiar with the sensation of fatigue, there are still profound divergences on what it represents and its mechanisms. Fatigue can take various forms depending on the condition in which it develops. Cancer-related fatigue is considered a symptom of exhaustion that is often present at the time of diagnosis, increases in intensity during cancer therapy, and does not always recede after completion of treatment. It is usually attributed to the inflammation induced by damage-associated molecular patterns released by tumor cells during cancer progression and in response to its treatment. In this review, we argue that it is necessary to go beyond the symptoms of fatigue to understand its nature and mechanisms. We propose to consider fatigue as a psychobiological process that regulates the behavioral activities an organism engages in to satisfy its needs, according to its physical ability to do so and to the capacity of its intermediary metabolism to exploit the resources procured by these activities. This last aspect is critical as it implies that these metabolic aspects need to be considered to understand fatigue. Based on the findings we have accumulated over several years of studying fatigue in diverse murine models of cancer, we show that energy metabolism plays a key role in the development and persistence of this condition. Cancer-related fatigue is dependent on the energy requirements of the tumor and the negative impact of cancer therapy on the mitochondrial function of the host. When inflammation is present, it adds to the organism\u27s energy expenses. The organism needs to adjust its metabolism to the different forms of cellular stress it experiences thanks to specialized communication factors known as mitokines that act locally and at a distance from the cells in which they are produced. They induce the subjective, behavioral, and metabolic components of fatigue by acting in the brain. Therefore, the targeting of mitokines and their brain receptors offers a window of opportunity to treat fatigue when it is no longer adaptive but an obstacle to the quality of life of cancer survivors
Ferroptosis regulates hemolysis in stored murine and human red blood cells.
No full textRed blood cell (RBC) metabolism regulates hemolysis during aging in vivo and in the blood bank. However, the genetic underpinnings of RBC metabolic heterogeneity and extravascular hemolysis at population scale are incompletely understood. On the basis of the breeding of 8 founder strains with extreme genetic diversity, the Jackson Laboratory diversity outbred population can capture the impact of genetic heterogeneity in like manner to population-based studies. RBCs from 350 outbred mice, either fresh or stored for 7 days, were tested for posttransfusion recovery, as well as metabolomics and lipidomics analyses. Metabolite and lipid quantitative trait loci (QTL) mapped \u3e400 gene-metabolite associations, which we collated into an online interactive portal. Relevant to RBC storage, we identified a QTL hotspot on chromosome 1, mapping on the region coding for the ferrireductase 6-transmembrane epithelial antigen of the prostate 3 (Steap3), a transcriptional target to p53. Steap3 regulated posttransfusion recovery, contributing to a ferroptosis-like process of lipid peroxidation, as validated via genetic manipulation in mice. Translational validation of murine findings in humans, STEAP3 polymorphisms were associated with RBC iron content, lipid peroxidation, and in vitro hemolysis in 13 091 blood donors from the Recipient Epidemiology and Donor Evaluation Study. QTL analyses in humans identified a network of gene products (fatty acid desaturases 1 and 2, epoxide hydrolase 2, lysophosphatidylcholine acetyl-transferase 3, solute carrier family 22 member 16, glucose 6-phosphate dehydrogenase, very long chain fatty acid elongase, and phospholipase A2 group VI) associated with altered levels of oxylipins. These polymorphisms were prevalent in donors of African descent and were linked to allele frequency of hemolysis-linked polymorphisms for Steap3 or p53. These genetic variants were also associated with lower hemoglobin increments in thousands of single-unit transfusion recipients from the vein-to-vein database