Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.

Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyze the transmission of early pre-gastrulation lineages and corresponding mutations across human generations.

Dissecting transcriptome signals of anti-PD-1 response in lung adenocarcinoma.

Immune checkpoint blockades are actively adopted in diverse cancer types including metastatic melanoma and lung cancer. Despite of durable response in 20-30% of patients, we still lack molecular markers that could predict the patient responses reliably before treatment. Here we present a composite model for predicting anti-PD-1 response based on tumor mutation burden (TMB) and transcriptome sequencing data of 85 lung adenocarcinoma (LUAD) patients who received anti-PD-(L)1 treatment.

Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline.

Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyzed the transmission of early pregastrulation lineages and corresponding mutations across human generations.

Genomic data resources of the Brain Somatic Mosaicism Network for neuropsychiatric diseases.

Somatic mosaicism is defined as an occurrence of two or more populations of cells having genomic sequences differing at given loci in an individual who is derived from a single zygote. It is a characteristic of multicellular organisms that plays a crucial role in normal development and disease. To study the nature and extent of somatic mosaicism in autism spectrum disorder, bipolar disorder, focal cortical dysplasia, schizophrenia, and Tourette syndrome, a multi-institutional consortium called the Brain Somatic Mosaicism Network (BSMN) was formed through the National Institute of Mental Health (NIMH).

Metagenome-assembled genomes of the GU0601 sample (the Han River, South Korea).

We generated metagenome sequences of the GU0601 sample collected from the Han River and constructed metagenome-assembled genomes (MAGs) to identify their bacterial composition. We identified six MAGs belonging to Alphaproteobacteria, Cyanobacteria, and Flavobacteria.

Efficient reconstruction of cell lineage trees for cell ancestry and cancer.

Mosaic mutations can be used to track cell ancestries and reconstruct high-resolution lineage trees during cancer progression and during development, starting from the first cell divisions of the zygote. However, this approach requires sampling and analyzing the genomes of multiple cells, which can be redundant in lineage representation, limiting the scalability of the approach. We describe a strategy for cost- and time-efficient lineage reconstruction using clonal induced pluripotent stem cell lines from human skin fibroblasts.

Correction: All2: A tool for selecting mosaic mutations from comprehensive multi-cell comparisons.

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

Analysis of somatic mutations in 131 human brains reveals aging-associated hypermutability.

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions.

Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling.

Patient-derived cells hold great promise for precision medicine approaches in human health. Human dermal fibroblasts have been a major source of cells for reprogramming and differentiating into specific cell types for disease modeling. Postmortem human dura mater has been suggested as a primary source of fibroblasts for in vitro modeling of neurodegenerative diseases.

All2: A tool for selecting mosaic mutations from comprehensive multi-cell comparisons.

Accurate discovery of somatic mutations in a cell is a challenge that partially lays in immaturity of dedicated analytical approaches. Approaches comparing a cell's genome to a control bulk sample miss common mutations, while approaches to find such mutations from bulk suffer from low sensitivity. We developed a tool, All2, which enables accurate filtering of mutations in a cell without the need for data from bulk(s).

Comprehensive identification of somatic nucleotide variants in human brain tissue.

Background: Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells.

Early developmental asymmetries in cell lineage trees in living individuals.

Mosaic mutations can be used to track cell lineages in humans. We used cell cloning to analyze embryonic cell lineages in two living individuals and a postmortem human specimen. Of 10 reconstructed postzygotic divisions, none resulted in balanced contributions of daughter lineages to tissues.

Complex mosaic structural variations in human fetal brains.

Somatic mosaicism, manifesting as single nucleotide variants (SNVs), mobile element insertions, and structural changes in the DNA, is a common phenomenon in human brain cells, with potential functional consequences. Using a clonal approach, we previously detected 200-400 mosaic SNVs per cell in three human fetal brains (15-21 wk postconception). However, structural variation in the human fetal brain has not yet been investigated.

CaPSSA: visual evaluation of cancer biomarker genes for patient stratification and survival analysis using mutation and expression data.

Summary: Predictive biomarkers for patient stratification play critical roles in realizing the paradigm of precision medicine. Molecular characteristics such as somatic mutations and expression signatures represent the primary source of putative biomarker genes for patient stratification. However, evaluation of such candidate biomarkers is still cumbersome and requires multistep procedures especially when using massive public omics data.

An integrated clinical and genomic information system for cancer precision medicine.

Background: Increasing affordability of next-generation sequencing (NGS) has created an opportunity for realizing genomically-informed personalized cancer therapy as a path to precision oncology. However, the complex nature of genomic information presents a huge challenge for clinicians in interpreting the patient's genomic alterations and selecting the optimum approved or investigational therapy. An elaborate and practical information system is urgently needed to support clinical decision as well as to test clinical hypotheses quickly.

MONGKIE: an integrated tool for network analysis and visualization for multi-omics data.

Background: Network-based integrative analysis is a powerful technique for extracting biological insights from multilayered omics data such as somatic mutations, copy number variations, and gene expression data. However, integrated analysis of multi-omics data is quite complicated and can hardly be done in an automated way. Thus, a powerful interactive visual mining tool supporting diverse analysis algorithms for identification of driver genes and regulatory modules is much needed.

CDA: combinatorial drug discovery using transcriptional response modules.

Background: Anticancer therapies that target single signal transduction pathways often fail to prevent proliferation of cancer cells because of overlapping functions and cross-talk between different signaling pathways. Recent research has identified that balanced multi-component therapies might be more efficacious than highly specific single component therapies in certain cases. Ideally, synergistic combinations can provide 1) increased efficacy of the therapeutic effect 2) reduced toxicity as a result of decreased dosage providing equivalent or increased efficacy 3) the avoidance or delayed onset of drug resistance.

Rational drug repositioning guided by an integrated pharmacological network of protein, disease and drug.

Background: The process of drug discovery and development is time-consuming and costly, and the probability of success is low. Therefore, there is rising interest in repositioning existing drugs for new medical indications. When successful, this process reduces the risk of failure and costs associated with de novo drug development.

hiPathDB: a human-integrated pathway database with facile visualization.

One of the biggest challenges in the study of biological regulatory networks is the systematic organization and integration of complex interactions taking place within various biological pathways. Currently, the information of the biological pathways is dispersed in multiple databases in various formats. hiPathDB is an integrated pathway database that combines the curated human pathway data of NCI-Nature PID, Reactome, BioCarta and KEGG.