Mechanisms driving epigenetic and transcriptional responses of microglia in a neurodegenerative lysosomal storage disorder model.

Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders (LSDs) and is associated with various age-related neurodegenerative diseases , but there is limited understanding of the mechanisms by which altered lysosomal function leads to changes in gene expression that drive pathogenic cellular phenotypes. To investigate this question, we performed systematic imaging, transcriptomic, and epigenetic studies of major brain cell types in null (KO) mice, a preclinical mouse model for Sanfilippo syndrome (Mucopolysaccharidosis Type IIIA, MPS-IIIA) . MPS-IIIA is a neurodegenerative LSD caused by homozygous loss-of-function (LoF) mutations in which results in severe early-onset developmental, behavioral, and neurocognitive impairment .

Discovering Genetic Modulators of the Protein Homeostasis System through Multilevel Analysis.

Every protein progresses through a natural lifecycle from birth to maturation to death; this process is coordinated by the protein homeostasis system. Environmental or physiological conditions trigger pathways that maintain the homeostasis of the proteome. An open question is how these pathways are modulated to respond to the many stresses that an organism encounters during its lifetime.

A cross-ancestry genome-wide meta-analysis, fine-mapping, and gene prioritization approach to characterize the genetic architecture of adiponectin.

Previous genome-wide association studies (GWASs) for adiponectin, a complex trait linked to type 2 diabetes and obesity, identified >20 associated loci. However, most loci were identified in populations of European ancestry, and many of the target genes underlying the associations remain unknown. We conducted a cross-ancestry adiponectin GWAS meta-analysis in ≤46,434 individuals from the Metabolic Syndrome in Men (METSIM) cohort and the ADIPOGen and AGEN consortiums.

Model-based identification of conditionally-essential genes from transposon-insertion sequencing data.

The understanding of bacterial gene function has been greatly enhanced by recent advancements in the deep sequencing of microbial genomes. Transposon insertion sequencing methods combines next-generation sequencing techniques with transposon mutagenesis for the exploration of the essentiality of genes under different environmental conditions. We propose a model-based method that uses regularized negative binomial regression to estimate the change in transposon insertions attributable to gene-environment changes in this genetic interaction study without transformations or uniform normalization.

Esophageal Microbiome in Healthy Children and Esophageal Eosinophilia.

Objectives: There is limited knowledge about the role of esophageal microbiome in pediatric esophageal eosinophilia (EE). We aimed to characterize the esophageal microbiome in pediatric patients with and without EE.

Methods: In the present prospective study, esophageal mucosal biopsies were obtained from 41 children.

A BAYESIAN NONPARAMETRIC MODEL FOR INFERRING SUBCLONAL POPULATIONS FROM STRUCTURED DNA SEQUENCING DATA.

There are distinguishing features or "hallmarks" of cancer that are found across tumors, individuals, and types of cancer, and these hallmarks can be driven by specific genetic mutations. Yet, within a single tumor there is often extensive genetic heterogeneity as evidenced by single-cell and bulk DNA sequencing data. The goal of this work is to jointly infer the underlying genotypes of tumor subpopulations and the distribution of those subpopulations in individual tumors by integrating single-cell and bulk sequencing data.

SCSIM: Jointly simulating correlated single-cell and bulk next-generation DNA sequencing data.

Background: Recently, it has become possible to collect next-generation DNA sequencing data sets that are composed of multiple samples from multiple biological units where each of these samples may be from a single cell or bulk tissue. Yet, there does not yet exist a tool for simulating DNA sequencing data from such a nested sampling arrangement with single-cell and bulk samples so that developers of analysis methods can assess accuracy and precision.

Results: We have developed a tool that simulates DNA sequencing data from hierarchically grouped (correlated) samples where each sample is designated bulk or single-cell.

Genomic data analysis workflows for tumors from patient-derived xenografts (PDXs): challenges and guidelines.

Background: Patient-derived xenograft (PDX) models are in vivo models of human cancer that have been used for translational cancer research and therapy selection for individual patients. The Jackson Laboratory (JAX) PDX resource comprises 455 models originating from 34 different primary sites (as of 05/08/2019). The models undergo rigorous quality control and are genomically characterized to identify somatic mutations, copy number alterations, and transcriptional profiles.

The Genome of C57BL/6J "Eve", the Mother of the Laboratory Mouse Genome Reference Strain.

Isogenic laboratory mouse strains enhance reproducibility because individual animals are genetically identical. For the most widely used isogenic strain, C57BL/6, there exists a wealth of genetic, phenotypic, and genomic data, including a high-quality reference genome (GRCm38.p6).

A Hypermorphic Allele Contributes to Impaired Thymic Deletion of Autoreactive Diabetogenic CD8 T Cells in NOD Mice.

In both NOD mice and humans, the development of type 1 diabetes (T1D) is dependent in part on autoreactive CD8 T cells recognizing pancreatic β cell peptides presented by often quite common MHC class I variants. Studies in NOD mice previously revealed that the common H2-K and/or H2-D class I molecules expressed by this strain aberrantly lose the ability to mediate the thymic deletion of pathogenic CD8 T cell responses through interactions with T1D susceptibility genes outside the MHC. A gene(s) mapping to proximal chromosome 7 was previously shown to be an important contributor to the failure of the common class I molecules expressed by NOD mice to mediate the normal thymic negative selection of diabetogenic CD8 T cells.

Use of Biosynthetic Controls as Performance Standards for Next-Generation Sequencing Assays of Somatic Tumors: A Multilaboratory Study.

Background: Next-generation sequencing (NGS) assays are highly complex tests that can vary substantially in both their design and intended application. Despite their innumerous advantages, NGS assays present some unique challenges associated with the preanalytical process, library preparation, data analysis, and reporting. According to a number of professional laboratory organization, control materials should be included both during the analytical validation phase and in routine clinical use to guarantee highly accurate results.

Genomes of the Mouse Collaborative Cross.

The Collaborative Cross (CC) is a multiparent panel of recombinant inbred (RI) mouse strains derived from eight founder laboratory strains. RI panels are popular because of their long-term genetic stability, which enhances reproducibility and integration of data collected across time and conditions. Characterization of their genomes can be a community effort, reducing the burden on individual users.

Whole-genome sequence of sungri/96 vaccine strain of peste des petits ruminants virus.

We report the complete genome sequence of the Sungri/96 vaccine strain of peste des petits ruminants virus (PPRV). The whole-genome nucleotide sequence has 89 to 99% identity with the available PPRV genome sequences in the NCBI database. This study helps to understand the epidemiological and molecular characteristics of the Sungri/96 strain.