Nature Genetics publishes the very highest quality research in genetics. It encompasses genetic and functional genomic studies on human traits and on other model organisms, including mouse, fly, nematode and yeast. Current emphasis is on the genetic basis for common and complex diseases and on the functional mechanism, architecture and evolution of gene networks, studied by experimental perturbation.
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Characterization of the mutational landscape of tumors is important to understanding disease etiology but does not provide mechanistic insight into the functional role of specific mutations. A new study introduces a statistical mechanical framework that draws on biophysical data from SH2 domain–phosphoprotein interactions to predict the functional effects of mutations in cancer.
A new study detects unstable nascent RNAs and uncovers thousands of transcription initiation sites in promoters and enhancers. Detailed analysis shows that these initiation sites have a similar architecture and that they are differentiated by post-transcriptional regulation rather than transcription initiation.
Febrile seizures can arise in response to fevers induced by viral infection or as an adverse reaction to live-virus vaccines such as measles, mumps and rubella (MMR) vaccination. A new study has now identified common genetic variants influencing susceptibility to febrile seizures, including two loci specifically associated with MMR-related events.
Erik Larsson and colleagues present an analysis pipeline for identifying likely transcription-altering noncoding somatic mutations in cancer using publicly available data from 505 tumor genomes across 14 cancer types. They find that TERT promoter mutations show strong associations to altered transcriptional levels and identify recurrent promoter mutations in DPH3 and PLEKHS1.
Levi Garraway and colleagues report the identification of somatic mutations of RNF43, which encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling, in over 18% of colorectal adenocarcinomas and endometrial carcinomas.
Tatsuhiro Shibata, David Wheeler, Hiroyuki Aburatani and colleagues report the genomic, exomic and oncoviral sequencing of hundreds of liver cancers from the United States and Japan. The authors analyzed mutation patterns and identified signatures unique to the Asian cases.
Bjarke Feenstra and colleagues identify common variants at six loci associated with
general or MMR vaccine–related febrile seizures. The two loci specifically
associated with MMR-related febrile seizures harbor the interferon-stimulated gene
IFI44L and the measles virus receptor gene CD46.
Andrew Jackson, Peter Nürnberg and colleagues identify mutations in PLK4 and TUBGCP6 in individuals with microcephaly, primordial dwarfism, retinopathy and other congenital anomalies. These findings extend the spectrum of human phenotypes associated with centriole dysfunction.
Evan Eichler and colleagues present a detailed characterization of the chromosome 15q13.3 microdeletion region. They identify complex structural polymorphisms and find that the rearrangement breakpoints cluster in palindromic GOLGA8 core duplicons, providing evidence that this repeat and its palindromic architecture underlie the evolutionary and disease-related instability of this region.
Ming Li, Ruiqiang Li and colleagues report the whole-genome sequencing of a male golden snub-nosed monkey, Rhinopithecus roxellana, as well as its relatives Rhinopithecus bieti, Rhinopithecus brelichi and Rhinopithecus strykeri. Their analysis provides insights into primate evolution and adaptation to a diet consisting primarily of leaves and seeds.
John Lis, Adam Siepel and colleagues map transcription start sites across the genome in two human cell lines using a nuclear run-on protocol called GRO-cap. They find a common architecture of initiation at both promoters and enhancers and that transcript elongation stability provides the strongest distinction between promoters and enhancers.
Astrid von Mentzer, Gordon Dougan and colleagues report the whole-genome sequencing of a representative global collection of enterotoxigenic Escherichia coli (ETEC), a major cause of infectious diarrhea, including samples from 20 countries isolated between 1980 and 2011. They find that, although ETEC isolates are widely distributed across the E. coli species and are genetically diverse, there are several discrete lineages that have contributed to overlapping global epidemics.
Holger Lerche, Camila Esguerra and colleagues report the identification of inactivating mutations in STX1B in individuals with various seizure-related disorders, including febrile seizures and epilepsy. Functional studies indicate that STX1B acts in the presynaptic release machinery.
Sarah Dunstan, Chiea Chuen Khor and colleagues identify common variants in the HLA-DRB1 region associated with resistance to enteric fever. Individuals carrying the protective variants exhibit roughly five-fold higher resistance against developing this life-threatening infectious disease.
Zachary Lippman and colleagues report the recovery in tomato of novel, chemically induced alleles in the SFT (florigen) gene and a newly identified suppressor of the SELF PRUNING gene. These alleles, in combination with previous florigen pathway mutations, allow for the quantitative fine-tuning of fruit yield, which may be applicable to other crop species.
Frank Steemers and colleagues report a new method for genome-wide haplotyping based on contiguity-preserving transposition and combinatorial indexing. They apply this method to assemble over 95% of the heterozygous variants in a human genome into long, accurate haplotype blocks.
David Jaffe and colleagues report a new algorithm, DISCOVAR, for variant calling and de novo genome assembly. They test the algorithm on a new reference variant call set and demonstrate improved variant calling, particularly in challenging regions of the genome.
Noah Zaitlen, Alkes Price and colleagues report a new approach to estimate the narrow-sense heritability of complex traits from unrelated individuals in a recently admixed population. They apply this approach to estimate the heritability for 13 quantitative or case-control phenotypes in 21,497 African-American individuals and suggest the inflation of family-based h2 estimates.
Peter Sorger, Mohammed AlQuraishi and colleagues present a statistical framework for integrating biophysical and genomic data to predict the consequences of cancer-related mutations on protein-protein interactions. They apply their framework to the SH2 phosphoprotein network using publicly available data from The Cancer Genome Atlas.