Distal enhancers play pivotal roles in development and disease yet remain one of the least understood regulatory elements. We used massively parallel reporter assays to perform functional comparisons of two leading enhancer models and find that gene-distal transcription start sites are robust predictors of active enhancers with higher resolution than histone modifications. We show that active enhancer

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Access to medical data is central for conducting research on genomics. However, to tap these metadata (observable traits and phenotypes, diagnoses and medication, and labels), researchers must grapple with the complex and sensitive nature of the information. In this Perspective, we argue that, at this exciting time for genomics and artificial intelligence, several critical aspects of data generation

We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10−11) independent association signals for 459 cell traits at 69 loci (52 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated

De novo DNA methylation (DNAme) in mammalian germ cells is dependent on DNMT3A and DNMT3L. However, oocytes and spermatozoa show distinct patterns of DNAme. In mouse oocytes, de novo DNAme requires the lysine methyltransferase (KMTase) SETD2, which deposits H3K36me3. We show here that SETD2 is dispensable for de novo DNAme in the male germline. Instead, the lysine methyltransferase NSD1, which broadly

Cancers accumulate mutations that lead to neoantigens, novel peptides that elicit an immune response, and consequently undergo evolutionary selection. Here we establish how negative selection shapes the clonality of neoantigens in a growing cancer by constructing a mathematical model of neoantigen evolution. The model predicts that, without immune escape, tumor neoantigens are either clonal or at low

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The WashU Virus Genome Browser is a web-based portal for efficient visualization of viral ‘omics’ data in the context of a variety of annotation tracks and host infection responses. The browser features both a phylogenetic-tree-based view and a genomic-coordinate, track-based view in which users can analyze the sequence features of viral genomes, sequence diversity among viral strains, genomic sites

The emergence of the COVID-19 pandemic has spurred a global rush to uncover basic biological mechanisms to inform effective vaccine and drug development. Despite the novelty of the virus, global sequencing efforts have already identified genomic variation across isolates. To enable easy exploration and spatial visualization of the potential implications of SARS-CoV-2 mutations in infection, host immunity

The UCSC SARS-CoV-2 Genome Browser (https://genome.ucsc.edu/covid19.html) is an adaptation of our popular genome-browser visualization tool for this virus, containing many annotation tracks and new features, including conservation with similar viruses, immune epitopes, RT–PCR and sequencing primers and CRISPR guides. We invite all investigators to contribute to this resource to accelerate research

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The role of N6-methyladenosine (m6A) is still not fully understood. Two new studies advance understanding of this RNA modification. One shows that m6A modification of nascent messenger RNA promotes transcription by recruiting the histone H3 K9 demethylase KDM3B. Another study identifies genetic variants that affect m6A deposition and human disease.

Binding of RNA to the gene expression regulator Polycomb repressive complex 2 (PRC2) has been proposed to antagonize PRC2’s chromatin recruitment. A new study now shows that RNA is in fact critical for correct recruitment of PRC2 at its target genes in human pluripotent stem cells and suggests that interplay of PRC2 and RNA can fine-tune PRC2’s regulatory role.

Increasing amounts of crop genomic resources, along with new technical achievements in genome analysis, can facilitate basic and translational research in agriculture, and expand the ability to meet the global challenge of food production and security.

Most cancer genomic data are generated from bulk samples composed of mixtures of cancer subpopulations, as well as normal cells. Subclonal reconstruction methods based on machine learning aim to separate those subpopulations in a sample and infer their evolutionary history. However, current approaches are entirely data driven and agnostic to evolutionary theory. We demonstrate that systematic errors

Animal chromosomes are partitioned into contact domains. Pathogenic domain disruptions can result from chromosomal rearrangements or perturbation of architectural factors. However, such broad-scale alterations are insufficient to define the minimal requirements for domain formation. Moreover, to what extent domains can be engineered is just beginning to be explored. In an attempt to create contact

FOXA1 functions as a pioneer transcription factor by facilitating the access to chromatin for steroid hormone receptors, such as androgen receptor and estrogen receptor1,2,3,4, but mechanisms regulating its binding to chromatin remain elusive. LSD1 (KDM1A) acts as a transcriptional repressor by demethylating mono/dimethylated histone H3 lysine 4 (H3K4me1/2)5,6, but also acts as a steroid hormone receptor

Large-scale whole-genome sequencing studies have enabled the analysis of rare variants (RVs) associated with complex phenotypes. Commonly used RV association tests have limited scope to leverage variant functions. We propose STAAR (variant-set test for association using annotation information), a scalable and powerful RV association test method that effectively incorporates both variant categories

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Extrachromosomal DNA (ecDNA) amplification promotes intratumoral genetic heterogeneity and accelerated tumor evolution1,2,3; however, its frequency and clinical impact are unclear. Using computational analysis of whole-genome sequencing data from 3,212 cancer patients, we show that ecDNA amplification frequently occurs in most cancer types but not in blood or normal tissue. Oncogenes were highly enriched

The identification of prostate stem/progenitor cells and characterization of the prostate epithelial cell lineage hierarchy are critical for understanding prostate cancer initiation. Here, we characterized 35,129 cells from mouse prostates, and identified a unique luminal cell type (termed type C luminal cell (Luminal-C)) marked by Tacstd2, Ck4 and Psca expression. Luminal-C cells located at the distal

A dynamic epigenome is critical for appropriate gene expression in development and health1,2,3,4,5. Central to this is the intricate process of transcription6,7,8,9,10,11, which integrates cellular signaling with chromatin changes, transcriptional machinery and modifications to messenger RNA, such as N6-methyladenosine (m6A), which is co-transcriptionally incorporated. The integration of these aspects

Gene nomenclature can be complicated, and the official naming of genes requires rational standards to avoid confusion and to maximize clarity. The HUGO Gene Nomenclature Committee has released updated guidelines for the naming of human genes, and we encourage the community to adopt these recommendations.

Standardized gene naming is crucial for effective communication about genes, and as genomics becomes increasingly important in health care, the need for a consistent language to refer to human genes becomes ever more essential. Here, we present the current HUGO Gene Nomenclature Committee (HGNC) guidelines for naming not only protein-coding genes but also RNA genes and pseudogenes, and we outline the

Genomes are highly organized in space and time. Compartments, topologically associating domains (TADs) and loops are three dimensional (3D) genome features that have been extensively studied. Among these three levels of organization, TADs have sparked the most debate. New microscopy data shed light on how TADs and their leaky borders contribute to gene regulation.

Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV+) individuals. No comprehensive profiling of cancer genomes, transcriptomes or epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV+, and performed extended mutation analysis on an additional 89 tumors. We

Certain mutagens, including the APOBEC3 (A3) cytosine deaminase enzymes, can create multiple genetic changes in a single event. Activity of A3s results in striking ‘mutation showers’ occurring near DNA breakpoints; however, less is known about the mechanisms underlying the majority of A3 mutations. We classified the diverse patterns of clustered mutagenesis in tumor genomes, which identified a new

Response and resistance to anticancer therapies vary due to intertumor and intratumor heterogeneity1. Here, we map differentially enriched G-quadruplex (G4) DNA structure-forming regions (∆G4Rs) in 22 breast cancer patient-derived tumor xenograft (PDTX) models. ∆G4Rs are associated with the promoters of highly amplified genes showing high expression, and with somatic single-nucleotide variants. Differences

The diversity of maize (Zea mays) is the backbone of modern heterotic patterns and hybrid breeding. Historically, US farmers exploited this variability to establish today’s highly productive Corn Belt inbred lines from blends of dent and flint germplasm pools. Here, we report de novo genome sequences of four European flint lines assembled to pseudomolecules with scaffold N50 ranging from 6.1 to 10

Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1,2,3,4,5. Here we examine the mechanism underlying chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1,

Epstein–Barr virus (EBV) is associated with several human malignancies including 8–10% of gastric cancers (GCs). Genome-wide analysis of 3D chromatin topologies across GC lines, primary tissue and normal gastric samples revealed chromatin domains specific to EBV-positive GC, exhibiting heterochromatin-to-euchromatin transitions and long-range human–viral interactions with non-integrated EBV episomes

Tumor initiation and progression are somatic evolutionary processes driven by the accumulation of genetic alterations, some of which confer selective fitness advantages to the host cell. This gene-centric model has shaped the field of cancer biology and advanced understanding of cancer pathophysiology. Importantly, however, each genotype encodes diverse phenotypic traits that permit acclimation to

Epigenetic processes govern prostate cancer (PCa) biology, as evidenced by the dependency of PCa cells on the androgen receptor (AR), a prostate master transcription factor. We generated 268 epigenomic datasets spanning two state transitions—from normal prostate epithelium to localized PCa to metastases—in specimens derived from human tissue. We discovered that reprogrammed AR sites in metastatic PCa

The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, thus raising the question of how the DNA methylome remains stable despite constant epigenetic drift. Here, we report that a clonal population of DNA (cytosine-5)-methyltransferase 1 (DNMT1)-only cells produces a heterogeneous methylome, which

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome

When the status quo in science continues to perpetuate ingrained systems of discrimination, inequality and racism, the beneficiaries of these systems must not only reexamine their collective practices but also redress historical injustices through consequential, concrete actions that will lead to change. We cannot focus only on the first steps of listening and learning to build a better, fairer scientific

How ‘difficult’ is it for somatic evolution to produce a cell that is capable of leaving the primary tumor and growing in a distant organ? In this issue, Reiter et al. assess genetic diversity across metastatic lesions and identify a tight selective bottleneck preceding distant metastasis.

Many chromatin-binding proteins and protein complexes that regulate transcription also bind RNA. One of these, Polycomb repressive complex 2 (PRC2), deposits the H3K27me3 mark of facultative heterochromatin and is required for stem cell differentiation. PRC2 binds RNAs broadly in vivo and in vitro. Yet, the biological importance of this RNA binding remains unsettled. Here, we tackle this question in

We developed cis-X, a computational method for discovering regulatory noncoding variants in cancer by integrating whole-genome and transcriptome sequencing data from a single cancer sample. cis-X first finds aberrantly cis-activated genes that exhibit allele-specific expression accompanied by an elevated outlier expression. It then searches for causal noncoding variants that may introduce aberrant

Pachytene Piwi-interacting RNAs (piRNAs) are abundant small non-coding RNAs expressed in mammalian germ lines. A new study indicates that, among the diverse pool of piRNA sequences, a small number act as highly selective guides that induce cleavage of coding and non-coding transcripts, thus promoting piRNA generation and regulating gene expression.

Pachytene PIWI-interacting RNAs (piRNAs), which comprise >80% of small RNAs in the adult mouse testis, have been proposed to bind and regulate target RNAs like microRNAs, cleave targets like short interfering RNAs or lack biological function altogether. Although piRNA pathway protein mutants are male sterile, no biological function has been identified for any mammalian piRNA-producing locus. Here,

Genetic correlation is a central parameter for understanding shared genetic architecture between complex traits. By using summary statistics from genome-wide association studies (GWAS), linkage disequilibrium score regression (LDSC) was developed for unbiased estimation of genetic correlations. Although easy to use, LDSC only partially utilizes LD information. By fully accounting for LD across the

The sharing of genomic data holds great promise in advancing precision medicine and providing personalized treatments and other types of interventions. However, these opportunities come with privacy concerns, and data misuse could potentially lead to privacy infringement for individuals and their blood relatives. With the rapid growth and increased availability of genomic datasets, understanding the

N6-methyladenosine (m6A) plays important roles in regulating messenger RNA processing. Despite rapid progress in this field, little is known about the genetic determinants of m6A modification and their role in common diseases. In this study, we mapped the quantitative trait loci (QTLs) of m6A peaks in 60 Yoruba (YRI) lymphoblastoid cell lines. We found that m6A QTLs are largely independent of expression

Propagation of clonal regulatory programs contributes to cancer development. It is poorly understood how epigenetic mechanisms interact with genetic drivers to shape this process. Here, we combine single-cell analysis of transcription and DNA methylation with a Luria–Delbrück experimental design to demonstrate the existence of clonally stable epigenetic memory in multiple types of cancer cells. Longitudinal

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The human genome can be segmented into topologically associating domains (TADs), which have been proposed to spatially sequester genes and regulatory elements through chromatin looping. Interactions between TADs have also been suggested, presumably because of variable boundary positions across individual cells. However, the nature, extent and consequence of these dynamic boundaries remain unclear.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Inversions play an important role in disease and evolution but are difficult to characterize because their breakpoints map to large repeats. We increased by sixfold the number (n = 1,069) of previously reported great ape inversions by using single-cell DNA template strand and long-read sequencing. We find that the X chromosome is most enriched (2.5-fold) for inversions, on the basis of its size and

We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis

Mammalian cells stably maintain high levels of DNA methylation despite expressing both positive (DNMT3A/B) and negative (TET1-3) regulators. Here, we analyzed the independent and combined effects of these regulators on the DNA methylation landscape using a panel of knockout human embryonic stem cell (ESC) lines. The greatest impact on global methylation levels was observed in DNMT3-deficient cells

The overwhelming majority of participants in current genetic studies are of European ancestry. To elucidate disease biology in the East Asian population, we conducted a genome-wide association study (GWAS) with 212,453 Japanese individuals across 42 diseases. We detected 320 independent signals in 276 loci for 27 diseases, with 25 novel loci (P < 9.58 × 10−9). East Asian–specific missense variants

Three-dimensional organization of the genome is important for transcriptional regulation1,2,3,4,5,6,7. In mammals, CTCF and the cohesin complex create submegabase structures with elevated internal chromatin contact frequencies, called topologically associating domains (TADs)8,9,10,11,12. Although TADs can contribute to transcriptional regulation, ablation of TAD organization by disrupting CTCF or the

TET2 and DNMT3A mutations lead to similar long-term outcomes in blood cancers despite the antagonistic biochemical functions of their encoded proteins. A new study highlights the opposing effects of TET2 and DNMT3A mutations in shaping the early erythroid or myeloid bias of hematopoietic progenitors.

One of the many consequences of the global COVID-19 pandemic is the need for the scientific community to adapt to the cancellation of conferences and events because of travel restrictions and social-distancing guidelines. We have seen a very swift conversion to online meetings, which have allowed for this established form of science communication to continue and opened new avenues for innovation in