Volume 54 Issue 10, October 2022

KCNK3 mutations identified in sleep apnea probands affect TASK-1 X-gate function. These changes lead to an increase in potassium current and open probability, as well as impaired sensitivity to G-protein-coupled receptor inhibitors.

Multi-modal single-cell sequencing enables mapping of mutant and wild-type human hematopoietic stem and progenitor cells within the same person, to define cellular phenotypic and epigenetic perturbations associated with clonal hematopoiesis.

Oncogenes commonly amplify on circular extrachromosomal DNA (ecDNA) molecules in cancer. We show that ecDNA shapes each of the foundational principles of Darwinian evolution — random inheritance by descent, enhanced variation through random segregation, and selection — and thereby promotes rapid genome change, treatment resistance and poor outcomes for patients with cancer.

This Perspective outlines ten challenges facing translation of psychiatric genetic findings into clinical practice.

SAIGE-GENE+ performs set-based rare variant association tests with improved type 1 error control and computational efficiency by collapsing ultra-rare variants and conducting multiple tests corresponding to different minor allele frequency cutoffs and annotations.

Cross-disorder genetic association analyses identify five loci differentiating attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Individuals diagnosed with both ADHD and ASD are double-loaded with genetic risk for both disorders.

The sc-linker is an analysis framework that combines genome-wide association study summary statistics, epigenomics and single-cell transcriptomes to identify disease-critical cell types and cellular processes across tissues and states.

Analyses of population-level variation in gene and enhancer expression in the human brain characterize the gene–enhancer regulome and the regulatory mechanisms of transcribed enhancers in neuropsychiatric diseases.

Nanopore sequencing is used to profile chromatin accessibility and DNA methylation on DNA molecules over 100 kb. Phasing analysis at the H19/IGF2 locus identifies a primate-specific enhancer driving biallelic IGF2 expression in specific cellular contexts.

Multi-modality single-cell sequencing determines genotype, transcriptome and methylome information in cells from individuals with DNMT3A R882 mutated clonal hematopoiesis, allowing for the comparison of mutant and wild-type cells from the same individuals.

Random segregation of extrachromosomal DNA contributes to intratumoral heterogeneity and facilitates the rapid adaptation of human tumor cells to anticancer drugs.

Heterozygous de novo gain-of-function mutations in KCNK3, which encodes the two-pore-domain K⁺ channel TASK-1, cause a channelopathy characterized by developmental delay with sleep apnea.

Implementation of a genomics-informed prebreeding strategy in a global winter wheat collection enhances the use of genebank accessions and uncovers the value of genetic resources for wheat improvement.

A high-quality genome assembly of pea cultivar ZW6 and pan-genome analyses provide insights into pea genome evolution and domestication as well as genomic resources for pea improvement.

Single-cell DNA sequencing data are generated from human neurons using primary template-directed amplification and analyzed using SCAN2, an improved genotyping tool. Indels are enriched in neuronal regulatory elements and may be deleterious.

scDRS associates individual cells in scRNA-seq with disease by scoring single-cell transcriptomes using GWAS gene signatures. Applied to 74 GWAS and 1.3 million single-cell profiles, scDRS identifies specific cellular subpopulations associated with these diseases.