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Activating HER2 mutations are shown to confer resistance to ER-directed therapies in patients with ER+ metastatic breast cancer. Drug resistance caused by HER2 mutations was overcome by combining ER-directed therapy with a HER2 kinase inhibitor.
Analysis of mutational asymmetry with respect to the direction of replication and transcription suggests that error-prone damage bypass on the lagging strand has a major role in human germline and cancer mutations.
The improved genome assemblies of allotetraploid cotton species Gossypium hirsutum and Gossypium barbadense provide insights into cotton evolution and inform the construction of introgression lines used to identify loci associated with fiber quality.
Individuals with biscuspid aortic valve and ascending aortic aneurysm show enrichment of rare variants in ROBO4. Functional studies suggest that ROBO4 mutations disrupt endothelial cell performance and contribute to pathological remodeling of aortic tissues.
Assembly of a pan-genome from 910 humans of African descent identifies 296.5 Mb of novel DNA mapping to 125,715 distinct contigs. This African pan-genome contains ~10% more DNA than the current human reference genome.
In zebrafish, cilia-driven flow of cerebrospinal fluid transports adrenergic signals that induce urotensin neuropeptides in spinal cord neurons. In turn, these neuropeptides activate their receptor on nearby muscle fibers, straightening the body axis.
Analysis of 1,007 sibling pairs from 251 families identifies 878 de novo mutations shared by siblings at 448 sites. Recurrence probability based on parental somatic mosaicism, sibling sharing, parent of origin, mutation type and genomic position can range from 0.011% to 28.5%.
Retinoic acid and BMP4 signaling, together with p63, contribute to dynamic long-range chromatin interactions during keratinocyte differentiation. TP63 decreases chromatin accessibility and promotes H3K27me3 accumulation at enhancers.
This study finds germline loss-of-function mutations in HAVCR2, which encodes the immune modulator TIM-3, in individuals with subcutaneous panniculitis-like T cell lymphomas and hemophagocytic lymphohistiocytosis, a life-threatening inflammatory condition.
Genome-wide association meta-analysis of data sets from Iceland and the UK identifies 16 new risk loci for osteoarthritis, including missense variants in SMO, IL11, and COL11A1.
A mapping approach that screens mutants in a sterile interspecific hybrid identifies the genetic determinants of differences in high-temperature growth between divergent Saccharomyces cerevisiae and Saccharomyces paradoxus yeast species.
Promoter capture Hi-C in colorectal cancer cells integrated with cancer genome and expression data identifies a noncoding, cis-regulatory element that is recurrently mutated in cancer, affecting ETV1 expression, cell viability and patient survival.
Fine-mapping and functional studies highlight potential causal risk variants for rheumatoid arthritis and type 1 diabetes, including missense variants at DNASE1L3, PTPN22, SH2B3, and TYK2, and noncoding variants at MEG3, CD28–CTLA4, and IL2RA.
Large-scale loss-of-function screens and TP53 saturation mutagenesis screens in human cancer cell lines suggest that mutational processes combine with phenotypic selection to shape the landscape of somatic mutations at the TP53 locus.
Genome-wide analyses identify 42 risk loci for diverticular disease, 39 of which are new. Genes in associated regions are enriched for expression in connective tissue cell types and are coexpressed with genes involved in vascular and mesenchymal biology.
This study identifies a set of critical dependency genes in MYCN-amplified neuroblastoma that make up the oncogenic transcriptional regulatory circuitry underlying cell state and tumor survival.
Genome-wide polygenic risk scores derived from GWAS data for five common diseases can identify subgroups of the population with risk approaching or exceeding that of a monogenic mutation.
EBS, which prevents premature flowering in Arabidopsis, is shown to bind H3K27me3 and H3K4me3 via different domains. Disruption of either EBS–H3K27me3 or EBS–H3K4me3 interaction induces early floral transition.
Large-scale association analyses identify 142 independent risk variants for atrial fibrillation. Pathway and functional enrichment analyses suggest that many of the putative risk genes act via cardiac structural remodeling.
A combined analysis of participants from the UK Biobank and the International Glaucoma Genetic Consortium identifies 85 new loci for intraocular pressure (IOP). Pathway analysis uncovers new pathways associated with both IOP and glaucoma.