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.
Community standards for data access, interoperability and metadata only make sense if data are creatively reused to further research. We are therefore inviting the submission of Analysis papers that reformat and integrate existing data sets to generate substantial novel insights into gene expression in cell differentiation transitions and different cell fates.
Clear cell renal cell carcinoma (CCRCC) is characterized by mutation of the VHL gene and loss of a segment of chromosome 3. A new study using multi-region exome sequencing has identified substantial intratumoral heterogeneity within large primary CCRCCs, which has profound implications for understanding tumor evolution and for developing effective therapies.
Sex chromosomes in mammals, birds, reptiles and fish represent many independent evolutionary events, but there is spectacular convergence and stunning parallels. A new study details the early stages of ZW differentiation and sex determination in a flatfish and the establishment of dosage compensation and sex reversal by epigenetic mechanisms including DNA methylation.
Cell fate regulation is a central component of maintaining tissue homeostasis, yet the mechanisms instructing cell division diversity in tissue-specific stem cells have not been well understood. A new study uncovers a central role for microtubule motor–regulating protein Lis1 in hematopoietic stem cell fate determination and in leukemogenesis.
Jonathan Pritchard, Guy Sella and colleagues report an analysis using population genetic models to show that recent human demography is likely to have had little impact on the average burden of deleterious mutations. They examine two large exome sequence datasets and find that individuals of west African and European ancestry carry similar burdens of damaging mutations.
Charles Swanton and colleagues used multiregion exome sequencing to study the evolutionary histories of ten clear cell renal cell carcinomas. They observed marked intratumoral heterogeneity in all cases, with extensive evidence of parallel evolution of tumor subclones and only a small number of truncal driver events.
Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.
Tannishtha Reya and colleagues show that Lis1, a key mediator of asymmetric cell division, is required for blood formation and hematopoietic stem cell function. The authors also show that the directed control of asymmetric division is a critical regulator of malignant hematopoietic development.
Songlin Chen and colleagues sequenced the whole genomes of a male (ZZ) and a female (ZW) Chinese half-smooth tongue sole, Cynoglossus semilaevis. Their analysis provides insights into the structure and evolution of the sex chromosomes and adaptation to the benthic lifestyle of this flatfish.
Makedonka Mitreva and colleagues report the genome sequence and transcriptome analysis of the hookworm Necator americanus, a prevalent soil-transmitted human parasite and the cause of necatoriasis. They develop a hookworm protein microarray to examine the host parasite interaction and immune response, tested on blood samples from 200 individuals in an endemic region.
Doil Choi and colleagues report the genome sequence of the hot pepper, Capsicum annuum, as well as the resequencing of two cultivated peppers and a wild species, Capsicum chinense. Comparative genomic analysis across Solanaceae provides insights into genome expansion, pungency, ripening and disease resistance in hot peppers.
Francis Drobniewski and colleagues report the whole-genome sequencing of 1,000 Mycobacterium tuberculosis strains obtained prospectively from patients over a 2-year period in Samara, Russia, a region with a high incidence of multidrug-resistant (MDR) tuberculosis. They compare these strains to a diverse panel of strains isolated from across the UK and characterize the patterns of the emergence and evolution of drug resistance.
Tao Cheng, Qian-fei Wang, Gang Huang and colleagues identify recurrent somatic loss-of-function mutations in SETD2 in individuals with acute leukemia. SETD2 encodes a histone H3K36 methyltransferase, and loss of SETD2 function causes global loss of H3K36 trimethylation and promotes leukemia stem cell self renewal.
Unnur Thorsteinsdottir, Kari Stefansson and colleagues identify low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes. The newly discovered variants include an intronic variant associated with altered expression of CCND2, two independent missense variants in PAM and a rare frameshift variant in PDX1.
Kálmán Tory, Corinne Antignac and colleagues report that a variant of NPHS2, encoding p.Arg229Gln, causes nephrotic syndrome only when present in trans with particular mutations in the 3′ coding region of NPHS2. Mechanistically, the authors show that these 3′ mutations behave as recessive alleles when present with wild-type NPHS2 but exert a dominant-negative effect on the p.Arg229Gln variant, resulting in protein mislocalization.
Stephen Bentley, Paul Turner and colleagues report whole-genome sequencing of 3,085 pneumococci collected from a densely sampled pneumococcal carriage cohort in a Thai refugee camp over a 3-year period. They provide a high-resolution analysis of natural pneumococcal evolution and bacterial recombination, identifying lineage-specific variation in recombination.
Jay Shendure, Greg Cooper and colleagues report a framework for annotation of genetic variation, Combined Annotation–Dependent Depletion (CADD), integrating diverse annotations into a single C score. They show that C scores correlate with annotations of functionality, pathogenicity and experimentally measured regulatory effects.