Research articles

Jos Jonkers, Lodewyk Wessels and colleagues use a Sleeping Beauty transposon mutagenesis screen to identify genes required for invasive lobular breast carcinoma formation (ILC) in mice. They find recurrent and mutually exclusive insertions in Myh9, Ppp1r12a, Ppp1r12b and Trp53bp2, which are implicated in the actin cytoskeleton regulation pathway and have been found to be altered in human ILC breast cancer.

Erwin Gelfand, Andrew Snow, Joshua Milner and colleagues identify heterozygous CARD11 mutations associated with severe atopic disease in eight individuals from four families. They further show that the mutant CARD11 proteins exhibit both loss-of-function and dominant-interfering activity and that the cellular defects in patient T cells can be partially rescued by supplementing with glutamine.

Ingileif Jonsdottir, Björn Nilsson, Kari Stefansson and colleagues perform a genome-wide association study for immunoglobulin levels in Icelandic and Swedish cohorts. They find 38 new variants associated with IgA, IgG, IgM or composite immunoglobulin traits and identify candidate genes underlying the regulation of immunoglobulin levels.

Danielle Posthuma and colleagues report a genome-wide association analysis for insomnia complaints in 113,006 individuals from the UK Biobank that identifies associations with variants near seven genes. They find evidence for sex-specific genetic architectures underlying genetic risk for insomnia and genetic correlations between insomnia complaints and psychiatric and metabolic traits.

Christoph Plass and colleagues investigate the transcriptomic and epigenomic changes induced by treatment with inhibitors of DNMT and HDAC in cancer cell lines. They observe large numbers of treatment-induced non-annotated TSSs (TINATs) encoded in long-terminal repeats that are normally repressed in most cell types.

Paul Lehner and colleagues identify an essential role for MORC2 in HUSH complex–mediated epigenetic silencing. They show that loss of MORC2 causes chromatin decompaction at HUSH-target loci and that a MORC2 mutation that causes Charcot–Marie–Tooth disease results in hyperactivation of HUSH-mediated repression in neuronal cells.

Salvatore Spicuglia and colleagues use a high-throughput reporter assay to identify a set of mammalian promoters, termed Epromoters, that display enhancer activity and have distinct genomic and epigenomic features. Through CRISPR–Cas9 gene editing experiments, they show that Epromoters are involved in long-range gene regulation in cis.

Etienne Bucher and colleagues use a combination of short- and long-read sequencing, along with optical mapping technologies, to produce the high-quality de novo assembly of the apple genome. They identify a new repetitive retrotransposon sequence and analyze DNA methylation data in relation to important agronomic traits.

Tianzhen Zhang, Xiongming Du and colleagues report whole-genome resequencing of 318 upland cotton (Gossypium hirsutum) accessions. They carried out genome-wide association analyses to identify loci associated with fiber quality, lint yield and resistance to Verticillium wilt, and identify two ethylene-pathway genes associated with the increased lint yield observed in improved cultivars.

Christina Curtis and colleagues simulate spatial tumor growth under different evolutionary models and compare their results to multiregion sequencing data. They find that it is possible to distinguish tumors driven by strong positive selection from those evolving neutrally or under weak selection and infer different evolutionary modes within and between tumor types.

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1. They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci.

By analyzing imputed genetic data for 42 human traits, Doug Speed and colleagues derive a model that describes how heritability varies with minor allele frequency, linkage disequilibrium and genotype certainty. Using this model, they show that common SNPs contribute substantially more heritability than previously thought.

Sudipto Roy, Carol Wicking, Carsten Bergmann and colleagues report that mutations in DZIP1L cause autosomal recessive polycystic kidney disease (ARPKD). Through studies of mouse and zebrafish models of DZIP1L loss of function, the authors demonstrate that DZIP1L is required for proper function of the periciliary diffusion barrier.

Rajeev Varshney and colleagues resequence the whole genomes of 292 pigeonpea (Cajanus cajan) cultivars, landraces and wild species. They find genomic regions that were likely targets of domestication and perform genome-wide association analysis to identify candidate genes for agriculturally relevant traits.

Julia Zeitlinger and Wanqing Shao use ChIP-nexus to study RNA polymerase II (Pol II) promoter pausing and its relation to the formation of new initiation complexes in Drosophila cells. They find that pausing affects the initiation of new transcripts and propose that paused RNA Pol II helps to prevent new initiation between transcription bursts.

Alex Kentsis and colleagues identify somatic genomic rearrangements in primary human rhabdoid tumors characterized by deletions and inversions involving PGBD5-specific signal sequences at their breakpoints. They further show that ectopic expression of PGBD5 in primary immortalized human cells is sufficient to promote cell transformation in vitro and in immunodeficient mice in vivo, thus defining PGBD5 as an oncogenic mutator and providing a plausible mechanism for site-specific DNA rearrangements in solid tumors.

Kian Peng Koh and colleagues report that TET1 regulates lineage-specific genes in the mouse postimplantation embryo, many of them independently of DNA methylation changes, through regulation of JMJD8 expression. They show that Tet1 deletion causes embryonic defects, which are partially penetrant in an inbred strain but fully lethal in non-inbred mice.

Victor Albert, Petri Auvinen, Ykä Helariutta, Jaakko Kangasjärvi and colleagues report the reference genome of the silver birch (Betula pendula) and resequencing of 150 birch individuals. They infer past population size crashes consistent with historical periods of climatic change and identify candidate targets of more recent positive selection.

Eugene Gladyshev and Nancy Kleckner report that the DNMT1-like cytosine methylase DIM-2 can mediate RIP (repeat-induced point mutation) through cytosine-to-thymine mutation of repetitive DNA in Neurospora crassa. They show that this process requires heterochromatin factors and propose a model whereby direct interactions between homologous double-stranded DNA can initiate the formation of heterochromatin.

Bradley Cairns, Douglas Carrell, Stephen Tapscott and colleagues transcriptionally profile human oocytes and preimplantation embryos and highlight DUX4-family proteins as activators of cleavage-stage genes and repetitive elements. They show that Dux expression converts mouse embryonic stem cells into two-cell (2C) embryo-like cells, thus suggesting mouse DUX and human DUX4 as drivers of the mammalian cleavage/2C state.