Mouse Genome Informatics: an integrated knowledgebase system for the laboratory mouse

Genetics, Journal Year: 2024, Volume and Issue: 227(1)

Published: March 26, 2024

Abstract Mouse Genome Informatics (MGI) is a federation of expertly curated information resources designed to support experimental and computational investigations into genetic genomic aspects human biology disease using the laboratory mouse as model system. The Database (MGD) Gene Expression (GXD) are core MGI databases that share data system architecture. serves central community resource integrated about genome features, variation, expression, gene function, phenotype, models acquired from peer-reviewed publications, author submissions, major bioinformatics resources. To facilitate integration standardization data, biocuration scientists annotate terms controlled metadata vocabularies biological ontologies (e.g. Mammalian Phenotype Ontology, Developmental Anatomy, Disease etc.), by applying international standards for gene, allele, strain nomenclature. basic scientists, translational researchers, providing access FAIR-compliant in both human-readable compute-ready formats. accessible at https://informatics.jax.org. Here, we present an overview types represented highlight recent enhancements with focus on new functionality MGD GXD.

Language: Английский

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Locus-level L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites

Cell Genomics, Journal Year: 2024, Volume and Issue: 4(2), P. 100498 - 100498

Published: Feb. 1, 2024

Long interspersed element 1 (L1) retrotransposons are implicated in human disease and evolution. Their global activity is repressed by DNA methylation, but deciphering the regulation of individual copies has been challenging. Here, we combine short- long-read sequencing to unveil L1 methylation heterogeneity across cell types, families, loci elucidate key principles involved. We find that youngest primate families specifically hypomethylated pluripotent stem cells placenta not most tumors. Locally, intronic intimately associated with gene transcription. Conversely, state can propagate proximal region up 300 bp. This phenomenon accompanied binding specific transcription factors, which drive expression chimeric transcripts. Finally, hypomethylation alone typically insufficient trigger due redundant silencing pathways. Our results illuminate epigenetic transcriptional interplay between their host genome.

Language: Английский

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Aging activates escape of the silent X chromosome in the female mouse hippocampus

Science Advances, Journal Year: 2025, Volume and Issue: 11(10)

Published: March 5, 2025

Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive (Xi) active (Xa), in contrast males with only Xa. Thus, reactivation of silent Xi genes may contribute differences. We use allele-specific, single-nucleus RNA sequencing show that aging remodels transcription the Xa across hippocampal cell types. Aging preferentially changed gene expression on X's relative autosomes. Select underwent activation, new escape cells including dentate gyrus, critical learning memory. Expression escapee Plp1, a myelin component, was increased hippocampus female mice parahippocampus women. AAV-mediated Plp1 elevation gyrus male improved cognition. Understanding how confer advantage could lead novel targets counter brain disease both sexes.

Language: Английский

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Defective Mammary Epithelial Outgrowth in Transgenic EKAREV–NLS Mice: Correction via Estrogen Supplementation and Genetic Background Modification

Journal of Mammary Gland Biology and Neoplasia, Journal Year: 2025, Volume and Issue: 30(1)

Published: Jan. 18, 2025

Language: Английский

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Into the Wild: A novel wild-derived inbred strain resource expands the genomic and phenotypic diversity of laboratory mouse models

PLoS Genetics, Journal Year: 2024, Volume and Issue: 20(4), P. e1011228 - e1011228

Published: April 10, 2024

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations over a century. However, mice capture only subset of genetic variation found in wild populations, ultimately limiting potential classical inbred strains to uncover phenotype-associated variants pathways. Wild populations are reservoirs diversity that could facilitate discovery new functional disease-associated alleles, but scarcity commercially available, well-characterized limits their broader adoption biomedical research. To overcome this barrier, we have recently developed, sequenced, phenotyped set 11 derived from wild-caught Mus musculus domesticus. Each these "Nachman strains" immortalizes unique haplotype sampled one five environmentally distinct locations across North South America. Whole genome sequence analysis reveals each strain carries between 4.73-6.54 million single nucleotide differences relative GRCm39 reference, with 42.5% Nachman genomes absent current panels. We on customized pipeline assess scope disease-relevant neurobehavioral, biochemical, physiological, metabolic, morphological trait variation. exhibit significant inter-strain >90% 1119 surveyed traits expand range phenotypic captured These novel wild-derived resources empower discoveries

Language: Английский

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GenomeMUSter mouse genetic variation service enables multitrait, multipopulation data integration and analysis

Genome Research, Journal Year: 2024, Volume and Issue: 34(1), P. 145 - 159

Published: Jan. 1, 2024

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function genetic variants that contribute disease. Thousands disease-relevant traits characterized in mice made publicly available. New including consomics, collaborative cross, expanded BXD, wild-derived add existing complex disease models, mapping populations, sensitized backgrounds for engineered mutations. The genome sequences strains, along with dense genotypes from others, enable integrated analysis trait–variant associations across but these analyses are hampered by sparsity Moreover, data not readily interoperable other resources. To address limitations, we created a uniformly variant resource harmonizing multiple sets. Missing were imputed using Viterbi algorithm data-driven technique incorporates local phylogenetic information, an approach is extendable model organisms. result web- programmatically accessible service called GenomeMUSter, comprising single-nucleotide covering 657 at 106.8 million segregating sites. Interoperation phenotype databases, analytic tools, resources wealth applications, multitrait, multipopulation meta-analysis. We show this cross-species comparisons type 2 diabetes substance use disorder meta-analyses, leveraging likely role human effects Other applications include refinement mapped loci prioritization strain modeling further unlock extant diversity genomic studies health

Language: Английский

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Small polymorphisms are a source of ancestral bias in structural variant breakpoint placement

Genome Research, Journal Year: 2024, Volume and Issue: 34(1), P. 7 - 19

Published: Jan. 1, 2024

High-quality genome assemblies and sophisticated algorithms have increased sensitivity for a wide range of variant types, breakpoint accuracy structural variants (SVs, ≥50 bp) has improved to near base pair precision. Despite these advances, many SV locations are subject systematic bias affecting representation. To understand why breakpoints inconsistent across samples, we reanalyzed 64 phased haplotypes constructed from long-read released by the Human Genome Structural Variation Consortium (HGSVC). We identify 882 insertions 180 deletions with variable not anchored in tandem repeats (TRs) or segmental duplications (SDs). SVs called aligned sequencing reads increase disagreements 2×–16×. Sequence had minimal impact on breakpoints, but observe strong effect ancestry. confirm that SNP indel polymorphisms enriched at shifted also absent callsets. Breakpoint homology increases likelihood imprecise calls distance they shifted, most heavily affected SVs. Because graph methods normalize investigated graphs generated two different find resulting other technical biases accuracy. The inconsistencies characterize affect ∼5% human can interpretation annotation. These limitations underscore need algorithm development improve databases, mitigate ancestry value callsets investigating features.

Language: Английский

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The Evolutionary Interplay of Somatic and Germline Mutation Rates

Annual Review of Biomedical Data Science, Journal Year: 2024, Volume and Issue: 7(1), P. 83 - 105

Published: April 26, 2024

Novel sequencing technologies are making it increasingly possible to measure the mutation rates of somatic cell lineages. Accurate germline rate measurement have also been available for a decade, assess how this fundamental evolutionary parameter varies across tree life. Here, we review some classical theories about and evolution that were formulated using principles population genetics biology aging cancer. We find measurements, while still limited in phylogenetic diversity, seem consistent with theory selection preserve soma is proportional life span. However, make conflicting predictions regarding which species should most accurate DNA repair. Resolving conflict will require carefully measuring scale time division achieving better understanding pleiotropy among types.

Language: Английский

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Locus-resolution analysis of L1 regulation and retrotransposition potential in mouse embryonic development

Genome Research, Journal Year: 2023, Volume and Issue: 33(9), P. 1465 - 1481

Published: Sept. 1, 2023

Mice harbor ∼2800 intact copies of the retrotransposon Long Interspersed Element 1 (L1). The in vivo retrotransposition capacity an L1 copy is defined by both its sequence integrity and epigenetic status, including DNA methylation monomeric units constituting young mouse promoters. Locus-specific dynamics during development may therefore elucidate explain spatiotemporal niches endogenous but remain unresolved. Here, we interrogate efficiency fate source (donor) L1s, identified as mobile vivo. We show that promoter monomer loss consistently attenuates relative potential their offspring (daughter) insertions. also observe most donor/daughter pairs are efficiently methylated upon differentiation vitro. use Oxford Nanopore Technologies (ONT) long-read sequencing to resolve genome-wide at individual loci, revealing a distinctive "smile" pattern levels across region. Using Pacific Biosciences (PacBio) SMRT 5' RACE products, then examine parallel with transcription start site (TSS) distribution locus-specific resolution. Together, our results offer novel perspective on interplay between repression, evolution, genome stability.

Language: Английский

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Atp1a2 and Kcnj9 Are Candidate Genes Underlying Sensitivity to Oxycodone‐Induced Locomotor Activation and Withdrawal‐Induced Anxiety‐Like Behaviors in C57BL/6 Substrains

Genes Brain & Behavior, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 13, 2025

Opioid use disorder is heritable, yet its genetic etiology largely unknown. C57BL/6J and C57BL/6NJ mouse substrains exhibit phenotypic diversity in the context of limited which together can facilitate discovery. Here, we found mice were less sensitive to oxycodone (OXY)-induced locomotor activation versus a conditioned place preference paradigm. Narrow-sense heritability OXY-induced activity traits ranged from 0.22 0.31, implicating suitability for analysis. Quantitative trait locus (QTL) mapping an F2 cross identified chromosome 1 QTL explaining 7%-12% variance OXY locomotion anxiety-like withdrawal elevated plus maze. A second EPM behavior on 5 near Gabra2 (alpha-2 subunit GABA-A receptor) explained 9% variance. To narrow locus, generated recombinant lines spanning 163-181 Mb, captured withdrawal, fine-mapped 2.45-Mb region (170.16-172.61 Mb). Transcriptome analysis five, localized striatal cis-eQTL transcripts two confirmed at protein level (KCNJ9, ATP1A2). Kcnj9 codes potassium channel (GIRK3) that major effector mu opioid receptor signaling. Atp1a2 Na+/K+ ATPase enzyme regulates neuronal excitability shows functional adaptations following chronic administration. summarize, candidate genes underlying physiological behavioral properties opioids, with direct preclinical relevance investigators employing these widely used clinical human studies disorder.

Language: Английский

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