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A truncated angiotensin-converting enzyme 2 (ACE2) isoform that lacks domains required for severe acute respiratory syndrome coronavirus 2 binding exhibits tissue-specific expression patterns and is responsive to interferon stimulation, in contrast to full-length ACE2, which is unresponsive to interferons.
Super-resolution microscopy identifies sub-topologically associating domain (TAD) nanodomains and intercellular heterogeneity in TAD conformation and insulation. Cohesin or CTCF depletion regulates distinct types of chromatin contacts at the TAD but not nanodomain level.
Analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) with known recessive biallelic pathogenic mutations in one of 17 BBS genes shows an enrichment of rare nonsynonymous secondary variants in the same gene set, with significant over-representation of secondary alleles in chaperonin-encoding genes.
Genome-wide association analyses in the Japanese population and trans-ancestry meta-analyses identify new risk loci for coronary artery disease. A polygenic risk score derived from these findings identifies individuals with increased risk of long-term cardiovascular mortality.
Somatic mutational loads in cancer genomes change with chromatin domain boundaries. Different mutational processes lead to distinct somatic mutation distributions in active versus inactive domains, including during tumor evolution.
MR-JTI, a unified framework for joint-tissue imputation and Mendelian randomization, improves prediction performance in a tissue-dependent manner when applied to large-scale biobanks and meta-analysis data.
High-throughput chromosome conformation enhancer capture identifies dynamic enhancer networks that regulate differentiation of human mesenchymal stem cells. Transcription factors (TFs) at baited enhancers appear to stabilize TF binding at target enhancers.
Whole-genome sequence analysis of 172 indigenous African cattle from 16 breeds identifies 16 loci linked to environmental adaptations among crossbred animals, including a highly divergent locus in African taurine cattle putatively linked to trypanotolerance.
Haplotype-resolved assembly of a heterozygous diploid potato, RH89-039-16, and identification of deleterious mutations provide insights into the genome organization and breeding of a clonally propagated diploid species.
A genomic analysis of tumors in mice caused by known or suspected carcinogens shows that most carcinogens do not generate distinct mutational signatures.
Whole-exome sequencing of 250 parent–offspring trios identifies an enrichment of rare damaging de novo mutations in individuals with cerebral palsy and implicates genetically mediated dysregulation of early neuronal connectivity in the etiology of this disorder.
Computational analysis of over 9,000 cancer genomes, coupled with functional validation in cell lines, highlights combinations of mutations required for tumor progression. This integrated approach provides a framework to stratify patients on the basis of interdependent genetic aberrations.
A study of 580 tomato lines resulting from a cross between a wild desert-adapted species and a domesticated cultivar elucidates the genetic basis of gene expression and metabolite variation associated with fruit traits and defense against pathogens.
Multi-omic profiling of brain tissue from patients with Alzheimer’s disease (AD) identifies gains in H3K27ac and H3K9ac linked to transcription and disease pathways. Increasing H3K27ac and H3K9ac in a fly model of AD exacerbates neurodegeneration.
A massively parallel reporter assay (eSTARR-seq) shows that gene-distal transcription start sites can delineate active enhancers with higher resolution than histone modifications.
An analysis of 3,757 Sardinian genomes identifies 122 association signals for 459 immune cell traits at 69 loci. Some variants are associated with autoimmune disorders.
NSD1, which deposits H3K36me2, is a major regulator of DNA methylation in male but not in female gametogenesis. NSD1 safeguards against H3K27me3-associated transcriptional silencing.
Mathematical modeling of evolutionary dynamics of neoantigens and immune escape in growing tumors shows that strong negative selection for neoantigens inhibits tumor growth but also provides a strong selective pressure for the evolution of immune escape.
Mendelian randomization (MR) and colocalization analyses are used to estimate causal effects of 1,002 plasma proteins on 225 phenotypes. Evidence from drug developmental programs shows that target-indication pairs with MR and colocalization support were more likely to be approved, highlighting the value of this approach for prioritizing therapeutic targets.
MOBSTER is an approach for subclonal reconstruction of tumors from cancer genomics data on the basis of models that combine machine learning with evolutionary theory, thus leading to more accurate evolutionary histories of tumors.