Meta-analysis of single-cell RNA sequencing co-expression in human neural organoids reveals their high variability in recapitulating primary tissue.

Human neural organoids offer an exciting opportunity for studying inaccessible human-specific brain development; however, it remains unclear how precisely organoids recapitulate fetal/primary tissue biology. We characterize field-wide replicability and biological fidelity through a meta-analysis of single-cell RNA-sequencing data for first and second trimester human primary brain (2.95 million cells, 51 data sets) and neural organoids (1.

Preservation of co-expression defines the primary tissue fidelity of human neural organoids.

Human neural organoid models offer an exciting opportunity for studying often inaccessible human-specific brain development; however, it remains unclear how precisely organoids recapitulate fetal/primary tissue biology. Here, we characterize field-wide replicability and biological fidelity through a meta-analysis of single-cell RNA-sequencing data for first and second trimester human primary brain (2.95 million cells, 51 datasets) and neural organoids (1.

Variability of cross-tissue X-chromosome inactivation characterizes timing of human embryonic lineage specification events.

X-chromosome inactivation (XCI) is a random, permanent, and developmentally early epigenetic event that occurs during mammalian embryogenesis. We harness these features to investigate characteristics of early lineage specification events during human development. We initially assess the consistency of X-inactivation and establish a robust set of XCI-escape genes.

Is it time to change the reference genome?

The use of the human reference genome has shaped methods and data across modern genomics. This has offered many benefits while creating a few constraints. In the following opinion, we outline the history, properties, and pitfalls of the current human reference genome.

Population-based identity-by-descent mapping combined with exome sequencing to detect rare risk variants for schizophrenia.

Genome-wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants.

Strength of functional signature correlates with effect size in autism.

Background: Disagreements over genetic signatures associated with disease have been particularly prominent in the field of psychiatric genetics, creating a sharp divide between disease burdens attributed to common and rare variation, with study designs independently targeting each. Meta-analysis within each of these study designs is routine, whether using raw data or summary statistics, but combining results across study designs is atypical. However, tests of functional convergence are used across all study designs, where candidate gene sets are assessed for overlaps with previously known properties.

Identification of Two Heritable Cross-Disorder Endophenotypes for Tourette Syndrome.

Objective: Phenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts.

Method: Assessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies.

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.

De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.

Schizophrenia is a serious psychiatric disorder with a broadly undiscovered genetic etiology. Recent studies of de novo mutations (DNMs) in schizophrenia and autism have reinforced the hypothesis that rare genetic variation contributes to risk. We carried out exome sequencing on 57 trios with sporadic or familial schizophrenia.