Personalized Circulating Tumor DNA Biomarkers Dynamically Predict Treatment Response and Survival In Gynecologic Cancers.

Background: High-grade serous ovarian and endometrial cancers are the most lethal female reproductive tract malignancies worldwide. In part, failure to treat these two aggressive cancers successfully centers on the fact that while the majority of patients are diagnosed based on current surveillance strategies as having a complete clinical response to their primary therapy, nearly half will develop disease recurrence within 18 months and the majority will die from disease recurrence within 5 years. Moreover, no currently used biomarkers or imaging studies can predict outcome following initial treatment.

A Next Generation Multiscale View of Inborn Errors of Metabolism.

Inborn errors of metabolism (IEM) are not unlike common diseases. They often present as a spectrum of disease phenotypes that correlates poorly with the severity of the disease-causing mutations. This greatly impacts patient care and reveals fundamental gaps in our knowledge of disease modifying biology.

Correction: A Cytosine Methytransferase Modulates the Cell Envelope Stress Response in the Cholera Pathogen.

[This corrects the article DOI: 10.1371/journal.pgen.

Geospatial Resolution of Human and Bacterial Diversity with City-Scale Metagenomics.

The panoply of microorganisms and other species present in our environment influence human health and disease, especially in cities, but have not been profiled with metagenomics at a city-wide scale. We sequenced DNA from surfaces across the entire New York City (NYC) subway system, the Gowanus Canal, and public parks. Nearly half of the DNA (48%) does not match any known organism; identified organisms spanned 1,688 bacterial, viral, archaeal, and eukaryotic taxa, which were enriched for harmless genera associated with skin (e.

A Cytosine Methyltransferase Modulates the Cell Envelope Stress Response in the Cholera Pathogen [corrected].

DNA methylation is a key epigenetic regulator in all domains of life, yet the effects of most bacterial DNA methyltransferases on cellular processes are largely undefined. Here, we used diverse techniques, including bisulfite sequencing, transcriptomics, and transposon insertion site sequencing to extensively characterize a 5-methylcytosine (5mC) methyltransferase, VchM, in the cholera pathogen, Vibrio cholerae. We have comprehensively defined VchM's DNA targets, its genetic interactions and the gene networks that it regulates.

Deciphering H3K4me3 broad domains associated with gene-regulatory networks and conserved epigenomic landscapes in the human brain.

Regulators of the histone H3-trimethyl lysine-4 (H3K4me3) mark are significantly associated with the genetic risk architecture of common neurodevelopmental disease, including schizophrenia and autism. Typical H3K4me3 is primarily localized in the form of sharp peaks, extending in neuronal chromatin on average only across 500-1500 base pairs mostly in close proximity to annotated transcription start sites. Here, through integrative computational analysis of epigenomic and transcriptomic data based on next-generation sequencing, we investigated H3K4me3 landscapes of sorted neuronal and non-neuronal nuclei in human postmortem, non-human primate and mouse prefrontal cortex (PFC), and blood.

Molecular systems evaluation of oligomerogenic APP(E693Q) and fibrillogenic APP(KM670/671NL)/PSEN1(Δexon9) mouse models identifies shared features with human Alzheimer's brain molecular pathology.

Identification and characterization of molecular mechanisms that connect genetic risk factors to initiation and evolution of disease pathophysiology represent major goals and opportunities for improving therapeutic and diagnostic outcomes in Alzheimer's disease (AD). Integrative genomic analysis of the human AD brain transcriptome holds potential for revealing novel mechanisms of dysfunction that underlie the onset and/or progression of the disease. We performed an integrative genomic analysis of brain tissue-derived transcriptomes measured from two lines of mice expressing distinct mutant AD-related proteins.

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids.

Synchronized age-related gene expression changes across multiple tissues in human and the link to complex diseases.

Aging is one of the most important biological processes and is a known risk factor for many age-related diseases in human. Studying age-related transcriptomic changes in tissues across the whole body can provide valuable information for a holistic understanding of this fundamental process. In this work, we catalogue age-related gene expression changes in nine tissues from nearly two hundred individuals collected by the Genotype-Tissue Expression (GTEx) project.

An integrated map of structural variation in 2,504 human genomes.

Structural variants are implicated in numerous diseases and make up the majority of varying nucleotides among human genomes. Here we describe an integrated set of eight structural variant classes comprising both balanced and unbalanced variants, which we constructed using short-read DNA sequencing data and statistically phased onto haplotype blocks in 26 human populations. Analysing this set, we identify numerous gene-intersecting structural variants exhibiting population stratification and describe naturally occurring homozygous gene knockouts that suggest the dispensability of a variety of human genes.

Inferred miRNA activity identifies miRNA-mediated regulatory networks underlying multiple cancers.

Motivation: MicroRNAs (miRNAs) play a key role in regulating tumor progression and metastasis. Identifying key miRNAs, defined by their functional activities, can provide a deeper understanding of biology of miRNAs in cancer. However, miRNA expression level cannot accurately reflect miRNA activity.

Whole-genome sequencing identifies emergence of a quinolone resistance mutation in a case of Stenotrophomonas maltophilia bacteremia.

Whole-genome sequences for Stenotrophomonas maltophilia serial isolates from a bacteremic patient before and after development of levofloxacin resistance were assembled de novo and differed by one single-nucleotide variant in smeT, a repressor for multidrug efflux operon smeDEF. Along with sequenced isolates from five contemporaneous cases, they displayed considerable diversity compared against all published complete genomes. Whole-genome sequencing and complete assembly can conclusively identify resistance mechanisms emerging in S.

A robust blood gene expression-based prognostic model for castration-resistant prostate cancer.

Background: Castration-resistant prostate cancer (CRPC) is associated with wide variations in survival. Recent studies of whole blood mRNA expression-based biomarkers strongly predicted survival but the genes used in these biomarker models were non-overlapping and their relationship was unknown. We developed a biomarker model for CRPC that is robust, but also captures underlying biological processes that drive prostate cancer lethality.

Prediction of Causal Candidate Genes in Coronary Artery Disease Loci.

Objective: Genome-wide association studies have to date identified 159 significant and suggestive loci for coronary artery disease (CAD). We now report comprehensive bioinformatics analyses of sequence variation in these loci to predict candidate causal genes.

Approach And Results: All annotated genes in the loci were evaluated with respect to protein-coding single-nucleotide polymorphism and gene expression parameters.

Preparing the next generation of genomicists: a laboratory-style course in medical genomics.

The growing gap between the demand for genome sequencing and the supply of trained genomics professionals is creating an acute need to develop more effective genomics education. In response we developed "Practical Analysis of Your Personal Genome", a novel laboratory-style medical genomics course in which students have the opportunity to obtain and analyze their own whole genome. This report describes our motivations for and the content of a "practical" genomics course that incorporates personal genome sequencing and the lessons we learned during the first three iterations of this course.

Exploring the associations between microRNA expression profiles and environmental pollutants in human placenta from the National Children's Study (NCS).

The placenta is the principal regulator of the in utero environment, and disruptions to this environment can result in adverse offspring health outcomes. To better characterize the impact of in utero perturbations, we assessed the influence of known environmental pollutants on the expression of microRNA (miRNA) in placental samples collected from the National Children's Study (NCS) Vanguard birth cohort. This study analyzed the expression of 654 miRNAs in 110 term placentas.

Assembly and diploid architecture of an individual human genome via single-molecule technologies.

We present the first comprehensive analysis of a diploid human genome that combines single-molecule sequencing with single-molecule genome maps. Our hybrid assembly markedly improves upon the contiguity observed from traditional shotgun sequencing approaches, with scaffold N50 values approaching 30 Mb, and we identified complex structural variants (SVs) missed by other high-throughput approaches. Furthermore, by combining Illumina short-read data with long reads, we phased both single-nucleotide variants and SVs, generating haplotypes with over 99% consistency with previous trio-based studies.

Single molecule-level detection and long read-based phasing of epigenetic variations in bacterial methylomes.

Beyond its role in host defense, bacterial DNA methylation also plays important roles in the regulation of gene expression, virulence and antibiotic resistance. Bacterial cells in a clonal population can generate epigenetic heterogeneity to increase population-level phenotypic plasticity. Single molecule, real-time (SMRT) sequencing enables the detection of N6-methyladenine and N4-methylcytosine, two major types of DNA modifications comprising the bacterial methylome.

Motivations, concerns and preferences of personal genome sequencing research participants: Baseline findings from the HealthSeq project.

Whole exome/genome sequencing (WES/WGS) is increasingly offered to ostensibly healthy individuals. Understanding the motivations and concerns of research participants seeking out personal WGS and their preferences regarding return-of-results and data sharing will help optimize protocols for WES/WGS. Baseline interviews including both qualitative and quantitative components were conducted with research participants (n=35) in the HealthSeq project, a longitudinal cohort study of individuals receiving personal WGS results.

Improved integrative framework combining association data with gene expression features to prioritize Crohn's disease genes.

Genome-wide association studies in Crohn's disease (CD) have identified 140 genome-wide significant loci. However, identification of genes driving association signals remains challenging. Furthermore, genome-wide significant thresholds limit false positives at the expense of decreased sensitivity.

Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.

Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals.