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  1. Article ; Online: BiocMAP: a Bioconductor-friendly, GPU-accelerated pipeline for bisulfite-sequencing data.

    Eagles, Nicholas J / Wilton, Richard / Jaffe, Andrew E / Collado-Torres, Leonardo

    BMC bioinformatics

    2023  Volume 24, Issue 1, Page(s) 340

    Abstract: Background: Bisulfite sequencing is a powerful tool for profiling genomic methylation, an epigenetic modification critical in the understanding of cancer, psychiatric disorders, and many other conditions. Raw data generated by whole genome bisulfite ... ...

    Abstract Background: Bisulfite sequencing is a powerful tool for profiling genomic methylation, an epigenetic modification critical in the understanding of cancer, psychiatric disorders, and many other conditions. Raw data generated by whole genome bisulfite sequencing (WGBS) requires several computational steps before it is ready for statistical analysis, and particular care is required to process data in a timely and memory-efficient manner. Alignment to a reference genome is one of the most computationally demanding steps in a WGBS workflow, taking several hours or even days with commonly used WGBS-specific alignment software. This naturally motivates the creation of computational workflows that can utilize GPU-based alignment software to greatly speed up the bottleneck step. In addition, WGBS produces raw data that is large and often unwieldy; a lack of memory-efficient representation of data by existing pipelines renders WGBS impractical or impossible to many researchers.
    Results: We present BiocMAP, a Bioconductor-friendly methylation analysis pipeline consisting of two modules, to address the above concerns. The first module performs computationally-intensive read alignment using Arioc, a GPU-accelerated short-read aligner. Since GPUs are not always available on the same computing environments where traditional CPU-based analyses are convenient, the second module may be run in a GPU-free environment. This module extracts and merges DNA methylation proportions-the fractions of methylated cytosines across all cells in a sample at a given genomic site. Bioconductor-based output objects in R utilize an on-disk data representation to drastically reduce required main memory and make WGBS projects computationally feasible to more researchers.
    Conclusions: BiocMAP is implemented using Nextflow and available at http://research.libd.org/BiocMAP/ . To enable reproducible analysis across a variety of typical computing environments, BiocMAP can be containerized with Docker or Singularity, and executed locally or with the SLURM or SGE scheduling engines. By providing Bioconductor objects, BiocMAP's output can be integrated with powerful analytical open source software for analyzing methylation data.
    MeSH term(s) Humans ; Sequence Analysis, DNA ; Whole Genome Sequencing ; Sulfites ; Genomics
    Chemical Substances hydrogen sulfite (OJ9787WBLU) ; Sulfites
    Language English
    Publishing date 2023-09-13
    Publishing country England
    Document type Journal Article
    ZDB-ID 2041484-5
    ISSN 1471-2105 ; 1471-2105
    ISSN (online) 1471-2105
    ISSN 1471-2105
    DOI 10.1186/s12859-023-05461-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Postmortem human brain genomics in neuropsychiatric disorders--how far can we go?

    Jaffe, Andrew E

    Current opinion in neurobiology

    2016  Volume 36, Page(s) 107–111

    Abstract: Large-scale collection of postmortem human brain tissue and subsequent genomic data generation has become a useful approach for better identifying etiological factors contributing to neuropsychiatric disorders. In particular, studying genetic risk ... ...

    Abstract Large-scale collection of postmortem human brain tissue and subsequent genomic data generation has become a useful approach for better identifying etiological factors contributing to neuropsychiatric disorders. In particular, studying genetic risk variants in non-psychiatric controls can identify biological mechanisms of risk free from confounding factors related to epiphenomena of illness. While the field has begun moving towards cell type-specific analyses, homogenate brain tissue with accompanying cellular profiles, can still identify useful hypotheses for more focused experiments, particularly when the dysregulated cell types are unknown. Technological advances, larger sample sizes, and focused research questions can continue to further leverage postmortem human brain research to better identify and understand the molecular etiology of neuropsychiatric disorders.
    MeSH term(s) Autism Spectrum Disorder/genetics ; Autism Spectrum Disorder/metabolism ; Autopsy ; Bipolar Disorder/genetics ; Bipolar Disorder/metabolism ; Brain/metabolism ; Depressive Disorder, Major/genetics ; Depressive Disorder, Major/metabolism ; Epigenesis, Genetic ; Gene Expression Profiling ; Genomics/methods ; Humans ; Mental Disorders/genetics ; Mental Disorders/metabolism ; Schizophrenia/genetics ; Schizophrenia/metabolism
    Language English
    Publishing date 2016-02
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1078046-4
    ISSN 1873-6882 ; 0959-4388
    ISSN (online) 1873-6882
    ISSN 0959-4388
    DOI 10.1016/j.conb.2015.11.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: SCRAP: a bioinformatic pipeline for the analysis of small chimeric RNA-seq data.

    Mills, William T / Eadara, Sreenivas / Jaffe, Andrew E / Meffert, Mollie K

    RNA (New York, N.Y.)

    2022  

    Abstract: MicroRNAs (miRNAs) are small non-coding RNAs (sncRNAs) that function in post-transcriptional gene regulation through imperfect base pairing with mRNA targets which results in inhibition of translation and typically destabilization of bound transcripts. ... ...

    Abstract MicroRNAs (miRNAs) are small non-coding RNAs (sncRNAs) that function in post-transcriptional gene regulation through imperfect base pairing with mRNA targets which results in inhibition of translation and typically destabilization of bound transcripts. Sequence-based algorithms historically used to predict miRNA targets face inherent challenges in reliably reflecting in vivo interactions. Recent strategies have directly profiled miRNA-target interactions by crosslinking and ligation of sncRNAs to their targets within the RNA-induced silencing complex (RISC), followed by high throughput sequencing of the chimeric sncRNA:target RNAs. Despite the strength of these direct profiling approaches, standardized pipelines for effectively analyzing the resulting chimeric sncRNA:target RNA sequencing data are not readily available. Here we present SCRAP, a robust Small Chimeric RNA Analysis Pipeline for the bioinformatic processing of chimeric sncRNA:target RNA sequencing data. SCRAP consists of two parts, each of which are specifically optimized for the distinctive characteristics of chimeric small RNA sequencing reads: first, read processing and alignment and second, peak calling and annotation. We apply SCRAP to benchmark chimeric sncRNA:target RNA sequencing datasets generated by distinct molecular approaches, and compare SCRAP to existing chimeric RNA analysis pipelines. SCRAP has minimal hardware requirements, is cross-platform, and contains extensive annotation to broaden accessibility for processing small chimeric RNA sequencing data and enable insights about the targets of small non-coding RNAs in regulating diverse biological systems.
    Language English
    Publishing date 2022-10-31
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1241540-6
    ISSN 1469-9001 ; 1355-8382
    ISSN (online) 1469-9001
    ISSN 1355-8382
    DOI 10.1261/rna.079240.122
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cortical cellular diversity and development in schizophrenia.

    Price, Amanda J / Jaffe, Andrew E / Weinberger, Daniel R

    Molecular psychiatry

    2020  Volume 26, Issue 1, Page(s) 203–217

    Abstract: While a definitive understanding of schizophrenia etiology is far from current reality, an increasing body of evidence implicates perturbations in early development that alter the trajectory of brain maturation in this disorder, leading to abnormal ... ...

    Abstract While a definitive understanding of schizophrenia etiology is far from current reality, an increasing body of evidence implicates perturbations in early development that alter the trajectory of brain maturation in this disorder, leading to abnormal function in early childhood and adulthood. This atypical development likely arises from an interaction of many brain cell types that follow distinct developmental paths. Because both cellular identity and development are governed by the transcriptome and epigenome, two levels of gene regulation that have the potential to reflect both genetic and environmental influences, mapping "omic" changes over development in diverse cells is a fruitful avenue for schizophrenia research. In this review, we provide a survey of human brain cellular composition and development, levels of genomic regulation that determine cellular identity and developmental trajectories, and what is known about how genomic regulation is dysregulated in specific cell types in schizophrenia. We also outline technical challenges and solutions to conducting cell type-specific functional genomic studies in human postmortem brain.
    MeSH term(s) Brain/metabolism ; Brain/pathology ; Gene Expression Regulation ; Humans ; Schizophrenia/genetics ; Schizophrenia/pathology ; Transcriptome
    Language English
    Publishing date 2020-05-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-020-0775-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Genetic and epigenetic analysis of schizophrenia in blood-a no-brainer?

    Jaffe, Andrew E / Kleinman, Joel E

    Genome medicine

    2016  Volume 8, Issue 1, Page(s) 96

    Abstract: Several recent studies have investigated either genetic or epigenetic variation in schizophrenia. A recent study presents comprehensive analyses of blood samples to better characterize the combined role of genetic and epigenetic variation in ... ...

    Abstract Several recent studies have investigated either genetic or epigenetic variation in schizophrenia. A recent study presents comprehensive analyses of blood samples to better characterize the combined role of genetic and epigenetic variation in schizophrenia. While the paper identifies significant associations with schizophrenia risk and diagnosis, the potential relevance to the brain in schizophrenia is questionable.
    Language English
    Publishing date 2016-09-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 2484394-5
    ISSN 1756-994X ; 1756-994X
    ISSN (online) 1756-994X
    ISSN 1756-994X
    DOI 10.1186/s13073-016-0354-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Dysregulated systemic metabolism in a Down syndrome mouse model.

    Sarver, Dylan C / Xu, Cheng / Velez, Leandro M / Aja, Susan / Jaffe, Andrew E / Seldin, Marcus M / Reeves, Roger H / Wong, G William

    Molecular metabolism

    2022  Volume 68, Page(s) 101666

    Abstract: Objective: Trisomy 21 is one of the most complex genetic perturbations compatible with postnatal survival. Dosage imbalance arising from the triplication of genes on human chromosome 21 (Hsa21) affects multiple organ systems. Much of Down syndrome (DS) ... ...

    Abstract Objective: Trisomy 21 is one of the most complex genetic perturbations compatible with postnatal survival. Dosage imbalance arising from the triplication of genes on human chromosome 21 (Hsa21) affects multiple organ systems. Much of Down syndrome (DS) research, however, has focused on addressing how aneuploidy dysregulates CNS function leading to cognitive deficit. Although obesity, diabetes, and associated sequelae such as fatty liver and dyslipidemia are well documented in the DS population, only limited studies have been conducted to determine how gene dosage imbalance affects whole-body metabolism. Here, we conduct a comprehensive and systematic analysis of key metabolic parameters across different physiological states in the Ts65Dn trisomic mouse model of DS.
    Methods: Ts65Dn mice and euploid littermates were subjected to comprehensive metabolic phenotyping under basal (chow-fed) state and the pathophysiological state of obesity induced by a high-fat diet (HFD). RNA sequencing of liver, skeletal muscle, and two major fat depots were conducted to determine the impact of aneuploidy on tissue transcriptome. Pathway enrichments, gene-centrality, and key driver estimates were performed to provide insights into tissue autonomous and non-autonomous mechanisms contributing to the dysregulation of systemic metabolism.
    Results: Under the basal state, chow-fed Ts65Dn mice of both sexes had elevated locomotor activity and energy expenditure, reduced fasting serum cholesterol levels, and mild glucose intolerance. Sexually dimorphic deterioration in metabolic homeostasis became apparent when mice were challenged with a high-fat diet. While obese Ts65Dn mice of both sexes exhibited dyslipidemia, male mice also showed impaired systemic insulin sensitivity, reduced mitochondrial activity, and elevated fibrotic and inflammatory gene signatures in the liver and adipose tissue. Systems-level analysis highlighted conserved pathways and potential endocrine drivers of adipose-liver crosstalk that contribute to dysregulated glucose and lipid metabolism.
    Conclusions: A combined alteration in the expression of trisomic and disomic genes in peripheral tissues contribute to metabolic dysregulations in Ts65Dn mice. These data lay the groundwork for understanding the impact of aneuploidy on in vivo metabolism.
    MeSH term(s) Female ; Male ; Mice ; Animals ; Humans ; Down Syndrome/genetics ; Aneuploidy ; Obesity/genetics ; Obesity/complications ; Glucose Intolerance ; Lipid Metabolism/genetics
    Language English
    Publishing date 2022-12-29
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2708735-9
    ISSN 2212-8778 ; 2212-8778
    ISSN (online) 2212-8778
    ISSN 2212-8778
    DOI 10.1016/j.molmet.2022.101666
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: TrkB-dependent regulation of molecular signaling across septal cell types.

    Rodriguez, Lionel A / Tran, Matthew Nguyen / Garcia-Flores, Renee / Oh, Seyun / Phillips, Robert A / Pattie, Elizabeth A / Divecha, Heena R / Kim, Sun Hong / Shin, Joo Heon / Lee, Yong Kyu / Montoya, Carly / Jaffe, Andrew E / Collado-Torres, Leonardo / Page, Stephanie C / Martinowich, Keri

    Translational psychiatry

    2024  Volume 14, Issue 1, Page(s) 52

    Abstract: The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning, and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social ...

    Abstract The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning, and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's.
    MeSH term(s) Humans ; Neurodegenerative Diseases ; Signal Transduction ; Inflammation ; RNA ; Protein Kinases
    Chemical Substances tropomyosin kinase (EC 2.7.11.28) ; RNA (63231-63-0) ; Protein Kinases (EC 2.7.-)
    Language English
    Publishing date 2024-01-23
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2609311-X
    ISSN 2158-3188 ; 2158-3188
    ISSN (online) 2158-3188
    ISSN 2158-3188
    DOI 10.1038/s41398-024-02758-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Accounting for cellular heterogeneity is critical in epigenome-wide association studies.

    Jaffe, Andrew E / Irizarry, Rafael A

    Genome biology

    2014  Volume 15, Issue 2, Page(s) R31

    Abstract: Background: Epigenome-wide association studies of human disease and other quantitative traits are becoming increasingly common. A series of papers reporting age-related changes in DNA methylation profiles in peripheral blood have already been published. ...

    Abstract Background: Epigenome-wide association studies of human disease and other quantitative traits are becoming increasingly common. A series of papers reporting age-related changes in DNA methylation profiles in peripheral blood have already been published. However, blood is a heterogeneous collection of different cell types, each with a very different DNA methylation profile.
    Results: Using a statistical method that permits estimating the relative proportion of cell types from DNA methylation profiles, we examine data from five previously published studies, and find strong evidence of cell composition change across age in blood. We also demonstrate that, in these studies, cellular composition explains much of the observed variability in DNA methylation. Furthermore, we find high levels of confounding between age-related variability and cellular composition at the CpG level.
    Conclusions: Our findings underscore the importance of considering cell composition variability in epigenetic studies based on whole blood and other heterogeneous tissue sources. We also provide software for estimating and exploring this composition confounding for the Illumina 450k microarray.
    MeSH term(s) Aging/genetics ; CpG Islands/genetics ; DNA/blood ; DNA Methylation/genetics ; Epigenesis, Genetic ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide
    Chemical Substances DNA (9007-49-2)
    Language English
    Publishing date 2014-02-04
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2040529-7
    ISSN 1474-760X ; 1474-760X
    ISSN (online) 1474-760X
    ISSN 1474-760X
    DOI 10.1186/gb-2014-15-2-r31
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Hypermetabolism in mice carrying a near complete human chromosome 21.

    Sarver, Dylan C / Xu, Cheng / Rodriguez, Susana / Aja, Susan / Jaffe, Andrew E / Gao, Feng J / Delannoy, Michael / Periasamy, Muthu / Kazuki, Yasuhiro / Oshimura, Mitsuo / Reeves, Roger H / Wong, G William

    bioRxiv : the preprint server for biology

    2023  

    Abstract: The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using ... ...

    Abstract The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are due to sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca
    Language English
    Publishing date 2023-01-31
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.01.30.526183
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Hypermetabolism in mice carrying a near-complete human chromosome 21.

    Sarver, Dylan C / Xu, Cheng / Rodriguez, Susana / Aja, Susan / Jaffe, Andrew E / Gao, Feng J / Delannoy, Michael / Periasamy, Muthu / Kazuki, Yasuhiro / Oshimura, Mitsuo / Reeves, Roger H / Wong, G William

    eLife

    2023  Volume 12

    Abstract: The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using ... ...

    Abstract The consequences of aneuploidy have traditionally been studied in cell and animal models in which the extrachromosomal DNA is from the same species. Here, we explore a fundamental question concerning the impact of aneuploidy on systemic metabolism using a non-mosaic transchromosomic mouse model (TcMAC21) carrying a near-complete human chromosome 21. Independent of diets and housing temperatures, TcMAC21 mice consume more calories, are hyperactive and hypermetabolic, remain consistently lean and profoundly insulin sensitive, and have a higher body temperature. The hypermetabolism and elevated thermogenesis are likely due to a combination of increased activity level and sarcolipin overexpression in the skeletal muscle, resulting in futile sarco(endo)plasmic reticulum Ca
    MeSH term(s) Mice ; Humans ; Animals ; Muscle, Skeletal/metabolism ; Thermogenesis/genetics ; Energy Metabolism/physiology ; Proteolipids/metabolism ; Cytoplasm/metabolism ; Chromosomes, Human/metabolism ; Calcium/metabolism
    Chemical Substances Proteolipids ; Calcium (SY7Q814VUP)
    Language English
    Publishing date 2023-05-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.86023
    Database MEDical Literature Analysis and Retrieval System OnLINE

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