Volume 55 Issue 8, August 2023

Identifying the ways that a study sample is not representative is essential for maximizing the generalizability of findings to the population. A new method proposes discerning non-representativeness in large-scale genetic studies by comparing the genotypes of closely related participants.

The three-dimensional organization of mammalian chromosomes can regulate transcription. Whether transcription itself influences genome structure has remained a source of debate. Using sensitive genome-wide readouts, two recent studies describe the involvement of transcription on genome architecture by different mechanisms.

How the chromatin states of transposable elements (TEs) are controlled in development and disease is unclear. We present CARGO-BioID, a CRISPR-based proteomic approach to identify TE-associated proteins, and reveal an interplay between RNA N6-methyladenosine (m⁶A) and DNA methylation that is crucial for regulating TE activation and human embryonic stem cell (hESC) fate.

Through whole-genome sequencing of single molecules of circulating cell-free DNA, we found that tumor-derived mutations in cancer genomes are associated with regions of late replication timing and other chromatin features. These genome-wide analyses identified altered regional mutation profiles in people with cancer that distinguished them from people without cancer and reflected tumor burden during therapy.

Matched single-cell transcriptomic and epigenomic profiles obtained from human scalp reveal gene regulatory maps of diverse cell types in the hair follicle niche. Integrating these data with existing genome-wide association studies enabled prioritization of cell types, genes, and causal variants implicated in the pathobiology of androgenetic alopecia, eczema, and other complex traits.

Across multiple cancer types, hotspot mutations in SF3B1 confer selective sensitivity to multiple clinically available PARP inhibitors. This sensitivity is due to reduced levels of CINP specifically in SF3B1-mutant cells, which leads to a loss of the canonical replication stress response after challenge with PARP inhibitors.

Polygenic Priority Score (PoPS) prioritizes candidate effector genes at complex trait loci by integrating genome-wide association summary statistics with other data types. Combining PoPS with methods that leverage local genetic signals further improves the performance.

Analysis of exome sequencing data identifies a burden of rare coding variants in 19 genes associated with bone mineral density. Integrated analyses show convergence of common- and rare-variant signals and highlight likely effector genes influencing osteoporosis risk.

Single-cell RNA- and ATAC-seq analysis of human scalp biopsies characterizes the regulatory programs of heterogeneous cell types. Integration with genome-wide association studies of hair and skin diseases implicates critical cell types, transcription factors and candidate causal variants.

Somatic mutations are identified from circulating cell-free DNA using a single-molecule-based lowpass whole-genome sequencing method. The regional distribution of mutations can identify a tumor-specific mutational profile in patients with cancer and can be used to monitor patients through treatment.

SF3B1 mutations confer sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi). Mechanistically, this is independent of homologous recombination repair and instead relies on a defective replication stress response due to a reduction of the cyclin-dependent kinase 2 interacting protein (CINP). PARPi treatment of SF3B1 mutant (SF3B1^MUT) tumors leads to replication stress induced by increased fork origin firing and culminates in cell cycle stalling.

The N6-methyladenosine reader YTHDC2 recruits TET1 to remove 5-methylcytosine from LTR7/HERV-H loci in human embryonic stem cells. The YTHDC2/LTR7 pathway inhibits neural fate commitment.

CRISPRi-based screen identifies enhancers that nonlinearly regulate lineage-specifying transcription factors during definitive endoderm differentiation. A new CTCF-loop-constrained Interaction Activity (CIA) model is better at predicting functional enhancers than previous Hi-C-based enhancer–promoter contact frequency models.

Depletion of cohesin subunit RAD21 increases DNA breaks genome-wide, leading to translocations at cancer-mutated hotspot genes. RAD21 depletion leads to dormant origin firing and induces irregular replication timing.

G4access is a nuclease-based method for identifying DNA G-quadruplex forming regions genome-wide in open chromatin using sequencing. Application across a range of cell types and species highlights associations of G-quadruplexes with various epigenetic and regulatory features.

Perturbation of RNA polymerase II (Pol II) via chemical inhibition or dTAG-induced degradation and analysis using Micro-C and run-on sequencing show that enhancer–promoter contacts are dependent on transcription and stabilized by paused RNA Pol II.

GY3 encodes a LOG-like protein that acts as a 5′-ribonucleotide phosphohydrolase in cytokinin synthesis. A Gypsy solo-LTR insertion downregulates GY3 expression and shows the potential to enhance grain yield in rice.

Saccharomyces cerevisiae Reference Assembly Panel (ScRAP) comprising telomere-to-telomere assemblies of 142 strains representing phylogenetic and ecological diversity of the species characterizes its genome structural landscape.

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.

A new methodology to study participation genetics via analyzing shared and unshared genotypes is applied to the UK Biobank, suggesting that participating in genetic studies is a complex trait with a meaningful genetic component.