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Structural variants (SVs) contribute to the genetic architecture of many brain-related disorders. Here, the authors integrate SV calls from genome sequencing (n = 755) with RNA-seq data (n = 629) from post-mortem dorsal lateral prefrontal cortex to annotate the gene regulatory effects of SVs in the human brain and their potential to contribute to disease.

Here, the authors perform a meta-analysis in 26,699 people with seizures and 492,324 controls to identify 25 genome-wide significant copy-number variants. The discovered loci point to known disease genes and associations with clinical annotations.

This study presents a framework to evaluate rare and de novo variation from whole-genome sequencing (WGS). The work suggests that robust results from WGS studies will require large cohorts and strategies that consider the substantial multiple-testing burden.

Michael Talkowski and colleagues examine karyotypically balanced genomic rearrangement landscapes in the germline at single-nucleotide resolution. They find predominant roles for complex reorganization and non-homologous repair in such 'chromothripsis' processes, suggesting a mechanism of template switching and blunt-end ligation.

Structural variants (SVs) in human genomes contribute diversity and diseases. Here, the authors use a multi-platform strategy to generate haplotype-resolved SVs for three human parent–child trios.

Here the authors perturb genes linked to schizophrenia risk in human neurons. They find that single perturbations share common downstream effects on gene networks, while joint perturbations result in downstream effects being saturated.

Michael Talkowski, David FitzPatrick, Erica Davis and colleagues report rare inherited or de novo missense variants in SMCHD1 in arhinia patients. Some of the same mutations in SMCHD1 are known to cause a phenotypically distinct muscular dystrophy disorder, FSHD2, and the distinct clinical features of the two disorders suggests that additional genes interact with SMCHD1 to cause arhinia.

Michael Talkowski and colleagues analyze balanced chromosomal abnormalities in 273 individuals by whole-genome sequencing. Their findings suggest that sequence-level resolution improves prediction of clinical outcomes for balanced rearrangements and provides insight into pathogenic mechanisms such as altered gene regulation due to changes in chromosome topology.

A large empirical assessment of sequence-resolved structural variants from 14,891 genomes across diverse global populations in the Genome Aggregation Database (gnomAD) provides a reference map for disease-association studies, population genetics, and diagnostic screening.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Using sequencing and haplotype-resolved assembly of 65 diverse human genomes, complex regions including the major histocompatibility complex and centromeres are analysed.

Analysis of rare protein-truncating, damaging missense and copy number variants from exome sequencing of 63,237 individuals identifies 72 genes associated with autism spectrum disorder.

Drugs that modify RNA splicing are promising treatments for many genetic diseases. Here the authors show that deep learning strategies can predict drug targets, strongly supporting the use of in silico approaches to expand the therapeutic potential of drugs that modulate RNA splicing.

A genomic constraint map for the human genome constructed using data from 76,156 human genomes from the Genome Aggregation Database shows that non-coding constrained regions are enriched for regulatory elements and variants associated with complex diseases and traits.

Here, the authors present a multi-omic framework using single cell technology to identify non-coding genetic variants in cranial motor neuron disorders, offering insights into their genetic basis and methods for studying other Mendelian diseases.

The GREGoR consortium provides foundational resources and substrates for the future of rare disease genomics.

A catalogue of predicted loss-of-function variants in 125,748 whole-exome and 15,708 whole-genome sequencing datasets from the Genome Aggregation Database (gnomAD) reveals the spectrum of mutational constraints that affect these human protein-coding genes.

Ultra-deep mapping of genome organization uncovers precise nuclear compartments and diffuse CTCF loops. This work demonstrates that compartment domains segregate the 5′ and 3′ ends of genes and that CTCF loops create proximal structures.

Combined high-throughput protein engineering with machine learning to curate libraries of CRISPR genome-editing enzymes with distinct genome targeting properties is described.

Common polygenic variation at chromosome 16p and rare recurrent deletions of 16p11.2 influencing autism risk are associated with reduced expression of genes throughout the 16p region, suggesting functional convergence of rare and common variant effects.

GATK-gCNV uses a probabilistic model and inference framework to discover rare copy number variants (CNVs) from sequencing read-depth information. This algorithm is used to generate a reference catalog of rare coding CNVs in exome sequencing data from UK Biobank.

Using All of Us pilot data, the authors compared short- and long-read performance across medically relevant genes and showcased the utility of long reads to improve variant detection and phasing in easy and hard to resolve medically relevant genes.

The detection of structural variants can be difficult with short-read sequencing technology, especially when variants are highly complex. Here, the authors use a MinION nanopore sequencer to analyse two patient genomes and develop NanoSV to map known and novel structural variants in long read data.

16p11.2 CNVs are associated with neurodevelopmental disorders. Here, the authors show that 16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro.

Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes.

A strategy for inferring phase for rare variant pairs is applied to exome sequencing data for 125,748 individuals from the Genome Aggregation Database (gnomAD). This resource will aid interpretation of rare co-occurring variants in the context of recessive disease.

Whole-genome sequencing of matched serial tumours from patients identifies two key mutagenic factors (APOBEC3 and chemotherapy) and extrachromosomal DNA-forming structural variants that drive treatment resistance in urothelial cancer.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis.

Structural variants (SV) can accumulate in repeat-rich parts of the genome and transform them in unexpected ways. Here, with their new assembly-based genotyper (NAHRwhals), the authors verify multi-step SVs in 37 human loci and identify alleles at risk for copy-number variation.

Recurrent, reciprocal genomic disorders due to non-allelic homologous recombination (NAHR) are a major cause of human disease. The authors developed a CRISPR/Cas9 genome engineering method that directly targets segmental duplications and efficiently mimics the NAHR-mediated mechanism of microdeletion and microduplication that occurs in vivo using 16p11.2 and 15q13.3 as proof-of-principle models.

In a new study including 200 families who experienced perinatal death, adding genomic analyses to standard autopsies improved the identification of underlying pathogenic causes and informed genetic counseling.

Genes encoding members of mammalian SWI/SNF (BAF) complexes are frequently mutated in individuals with neurodevelopmental disorders (NDDs). Mutant NDD residues include some unique to NDD and those shared with human cancers, impacting key structural hubs.

Analysis of the FGF14-SCA27B repeat locus identifies a common 5′-flanking insertion that represents the major allele, is present exclusively on nonpathogenic alleles, enhances repeat stability and increases chromatin accessibility.

Targeted deletions of topologically associating domain boundaries in mice using CRISPR genome editing cause a range of disruptions to normal in vivo genome function and organismal development.