Research Briefing in 2022

We developed a CRISPR-based functional assay for genetic sequence variants found in human disease, probing their effects on cell proliferation, survival, motility and any physiological or pathological process measurable by fluorescence-activated cell sorting (FACS). The assay accurately assessed variant pathogenicity, drug responsiveness or resistance and mechanistic role in disease, in vitro and in vivo.

High-grade serous ovarian cancer, the most common form of the disease, is often fatal. This study investigated the genomic and immune characteristics of tumors from women who survived more than 10 years after their initial diagnosis, and compared them with short-term and moderate-term survivors.

Adult human kidney organoids or tubuloids are derived from an epithelial CD24⁺ subpopulation in the proximal nephron and can be utilized for advanced disease modeling of the most common hereditary kidney disease: autosomal dominant polycystic kidney disease.

Genome sequencing and analysis of public epigenomic data enabled the identification of disease-causing variants in a non-coding regulatory region of hexokinase 1 (HK1) in individuals with congenital hyperinsulinism. These variants caused inappropriate HK1 expression within pancreatic β-cells, which led to increased insulin secretion and hypoglycemia.

Cancer cells frequently amplify oncogenes on DNA molecules outside of chromosomes — extrachromosomal DNA. A technique adapted for isolation of extrachromosomal DNA, termed CRISPR-CATCH, enables analyses of its genetic and epigenetic compositions, which provides insights into its origin, structural diversity and mechanism of oncogene activation in cancer.

We present a high-resolution genomic variation map that greatly expands the sequence information for maize and its wild relatives in the Zea genus. Population genetics of Zea spp. provide a vast trove of adaptive alleles that are absent in maize, with the potential for accelerating future breeding by reintroducing genetic diversity.

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.

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.

Migration can increase regional differences in both DNA variants and environmental factors that are associated with socio-economic status. Without controlling for geography, associations between genes and complex traits will therefore include effects of environmental differences between high-income and low-income regions.

The genetic landscape of human induced pluripotent stem cells (iPSCs) is strongly influenced by the somatic cells of origin, and mutational signatures directly reflect pre-reprogramming and post-reprogramming mutagenic processes. BCOR mutations are recurrent and have functional consequences for the differentiation capacity of iPSCs.

In our study of 83 tissue samples from 31 patients with pancreatic cancer receiving different treatment regimens, we directly identified normal cells transitioning to a tumor state. Single-cell technologies enabled us to observe how the tumor and the surrounding environment work together to create a treatment-resistant niche.

We comprehensively define the genomic landscape of pediatric acute lymphoblastic leukemia (ALL) in the largest cohort assembled to date, and identify new driver genes and biological pathways that are targeted by genetic alteration. These findings serve as a road map to improve our understanding of disease development and identify therapeutic targets in pediatric ALL.

We generated a cattle genotype–tissue expression atlas (CattleGTEx) as part of the farm animal GTEx project. Analysis of 7,180 public RNA-sequencing samples revealed genetic variants that regulate the transcriptome across 23 distinct bovine tissues. Integrating these data with GWAS advances our understanding of the fundamental molecular mechanisms that underpin complex traits in cattle.

Across >150,000 individuals, we identified hundreds of genes associated with autism spectrum disorder (ASD) and atypical neurodevelopment. Most ASD-related genes were also associated with developmental delay. However, increased mutation rates in ASD and shared genetic risk with schizophrenia was observed for some genes, many of which are enriched in developing neurons.

In the zebrafish heart, several transient fibroblast types appear after injury. High-throughput lineage tracing revealed that injury-responsive fibroblasts are derived from two distinct lineage origins: the epicardium and the endocardium. Targeted cell-type-specific depletion showed that at least one fibroblast type has a critical role in heart regeneration.

Assemblies of hexaploid cultivated oat, and of close relatives of its diploid and tetraploid progenitors, have revealed its polyploid formation and subgenome evolution. These high-quality oat reference genomes will facilitate the discovery of candidate genes that underlie beneficial traits such as hulless grain and disease resistance.

Genetic and phenotypic analyses of data from over 400,000 participants in the UK Biobank identified 10 new loci associated with the development of clonal hematopoiesis and implicated DNA damage, oncogene signaling, telomere maintenance and blood cell homing in its pathogenesis. These findings can help to decipher the pathogenesis of clonal hematopoiesis and develop therapeutic approaches.

Systematic CRISPR screens in primary human T cells uncovered the upstream regulators of crucial immune genes — IL2RA, IL2 and CTLA4. Then, using RNA-seq and ATAC-seq in knockout T cells, we mapped the downstream target genes and non-coding cis-regulatory elements of key regulators, thereby revealing a regulatory network enriched for immune disease-associated genes.

By integrating single-cell and bulk transcriptomic analyses, we found that malignant cells belong to two major intrinsic epithelial subtypes. We propose a refined, three-tiered classification of colorectal cancer subtypes based on intrinsic epithelial subtypes, microsatellite instability status and the presence of fibrosis.