Articles in 2022

This study presents a method for constructing complex trait polygenic scores from rare variants and shows that a polygenic score combining common and rare variants improves the accuracy of diagnosis for type 2 diabetes based on hemoglobin A1C levels.

This Perspective addresses next steps to investigate the predictions that inhibition of APOBEC3-mediated mutagenesis may limit tumor heterogeneity, metastasis and drug resistance in a broad range of cancer types by highlighting gaps in our understanding of APOBEC3 biology in cancer and in healthy tissues and strategies to address them.

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.

Genome-wide analyses identify loci associated with nonalcoholic fatty liver disease, including rare, protective loss-of-function variants in MTARC1 and GPAM. Plasma proteomic analyses provide insight into proteins involved in disease pathogenesis.

The ability to predict gene-expression landscapes at single-cell resolution has long been a challenge in the field of genomics. We mapped whole-body single-cell transcriptomic landscapes of zebrafish, Drosophila, and earthworm using Microwell-seq. We propose the first sequence-based model, Nvwa, that can predict gene expression at single-cell resolution directly from genomic sequences.

Genome-wide analysis of self-reported dyslexia identifies 42 associated loci, including 27 not previously associated with cognitive traits. Dyslexia shows genetic correlation with ambidexterity but not neuroanatomical measures of language-related circuitry.

A high-density genomic variation map from 744 genomes encompassing maize and all wild taxa of the genus Zea reveals evidence of adaptive variation and provides a genus-wide resource of genetic diversity in Zea.

CRISPR-CATCH is used to isolate extrachromosomal DNA (ecDNA) molecules containing oncogenes from human cancer cells. CRISPR-CATCH followed by nanopore sequencing allows for methylation profiling, highlighting differences from the native chromosomal loci.

High-throughput experimental platforms have revolutionized the ability to profile biochemical and functional properties of biological sequences such as DNA, RNA and proteins. By collating several data modalities with customizable tracks rendered using intuitive visualizations, genome browsers enable an interactive and interpretable exploration of diverse types of genome profiling experiments and derived annotations. However, existing genome browser tracks are not well suited for intuitive visualization of high-resolution DNA sequence features such as transcription factor motifs. Typically, motif instances in regulatory DNA sequences are visualized as BED-based annotation tracks, which highlight the genomic coordinates of the motif instances but do not expose their specific sequences. Instead, a genome sequence track needs to be cross-referenced with the BED track to identify sequences of motif hits. Even so, quantitative information about the motif instances such as affinity or conservation as well as differences in base resolution from the consensus motif are not immediately apparent. This makes interpretation slow and challenging. This problem is compounded when analyzing several cellular states and/or molecular readouts (such as ATAC-seq and ChIP–seq) simultaneously, as coordinates of enriched regions (peaks) and the set of active transcription factor motifs vary across cell states.

Microwell-seq is used to generate single-cell, whole-body expression landscapes of zebrafish, Drosophila and earthworm. A deep-learning model, Nvwa, predicts gene expression from DNA sequence and identifies regulatory programs shared across eight species.

Loss of NECTIN1 is a frequent event in human melanoma and is associated with metastasis. NECTIN1 depletion modulates a switch from cell–cell adhesion to cell–matrix adhesion in response to low levels of IGF1 signaling from the microenvironment.

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.

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.

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.

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.

The ion channel NALCN regulates cell shedding in mice and enhances metastasis in mouse models of cancer. Disseminated cells without oncogenic mutations form normal structures at secondary sites, suggesting that cell shedding is a physiological process that is hijacked during tumorigenesis.

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.

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.

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.