Research articles

Iris Heid, Gonçalo Abecasis, Sudha Iyengar and colleagues report the results of a large genome-wide association meta-analysis of macular degeneration based on over 43,000 subjects. They identify 16 new risk loci, including some very rare coding variants.

Anneke den Hollander, Patsy Nishina and colleagues report heterozygous missense mutations in CTNNA1 in three families with butterfly-shaped pigment dystrophy. Ctnna1-mutant mice display a similar phenotype and show increased cell shedding and large multinucleated cells in the retinal pigment epithelium, suggesting defects in intercellular adhesion and cytokinesis.

William Greenleaf, Michael Snyder, Carlos Araya and colleagues use density-based clustering methods on ~4,700 exomes from 21 tumor types to detect significantly mutated regions (SMRs), which show recurrent alterations in coding and noncoding elements and often associate with changes in gene expression and signaling. Mutation frequencies in SMRs demonstrate that distinct protein regions are differentially mutated across tumor types.

Jessica Okosun, David Sabatini and colleagues identify recurrent RRAGC mutations in follicular lymphoma, resulting in activated mTORC1 signaling. The activating nature of the mutations, their existence within the dominant clone and their stability during disease progression support the potential of these mutations as promising candidates for targeted therapy.

Leif Andersson, Gregory Barsh and colleagues show that Dun camouflage color in horses is due to TBX3 expression in hair follicles, which causes asymmetric distribution of hair follicle melanocytes and reduced pigment deposition. They find that most domestic horses are more intensely pigmented (non-dun) owing to regulatory mutations impairing TBX3 expression in the hair follicle.

Cris Kuhlemeier and colleagues analyze the genetic basis for floral UV absorbance in Petunia species with either nocturnal or diurnal pollinators. They show that distinct mutations in the MYB-FL gene explain gain or loss of UV absorbance that correlates with bee-to-moth and moth-to-hummingbird pollination transitions.

Matthew Meyerson and colleagues identify focal amplifications of regions harboring super-enhancers near KLF5, USP12, PARD6B and MYC in epithelial cancers. CRISPR/Cas9-mediated repression or deletion of a MYC enhancer in a lung adenocarcinoma cell line with the enhancer amplification results in downregulation of MYC and its target genes and impaired anchorage-independent and clonogenic growth.

Natsuhiko Kumasaka, Andrew Knights and Daniel Gaffney develop a new statistical approach for association mapping that models genetic effects and accounts for biases in sequencing data in a single probabilistic framework. They apply this method to generate a map of chromatin accessibility QTLs and show how it can be used to fine-map regulatory variants and link distal regulatory elements with genes.

Matthew Hurles and colleagues sequence the genomes of three multi-sibling families and investigate the rates and spectra of germline mutation. Their analyses suggest that the mutation rate per cell division is higher during early embryogenesis than in post-pubertal spermatogenesis.

Matthew Stephens and colleagues present a method for visualizing geographic patterns in genetic population structure. They apply this method to data from elephant, human and Arabidopsis thaliana populations and illustrate its potential to highlight barriers and corridors to gene flow.

Yaniv Erlich and colleagues report a genome-wide survey of the contribution of short tandem repeats (STRs) to gene expression in humans and identify 2,060 significant expression STRs (eSTRs). They find that eSTRs contribute 10–15% of the cis heritability mediated by all common variants and are associated with various clinically relevant phenotypes.

Ivona Aksentijevich and colleagues identify heterozygous loss-of-function mutations in TNFAIP3 (encoding A20) in six unrelated families with early-onset systemic inflammation. Affected individuals exhibit increased expression of NF-κB–mediated proinflammatory cytokines, consistent with the established role of A20 as a potent inhibitor of the NF-κB signaling pathway.

Raif Geha, Louis Kunkel, Waleed Al-Herz and colleagues report a mutation in TFRC (encoding transferrin receptor 1, TfR1) that causes combined immunodeficiency characterized by impaired function of T and B cells in homozygous patients. Iron citrate rescued the lymphocyte defects in patient-derived cells and in a mouse model, demonstrating the importance of TfR1-mediated iron internalization in adaptive immunity.

Kerstin Meyer and colleagues analyze a breast cancer gene regulatory network generated using publicly available expression and ChIP-seq data sets. They identify a cluster of 36 regulons that are significantly enriched for known breast cancer risk-associated genes and propose the use of regulon activity for patient stratification.

Murat Günel and colleagues use an integrated genomic approach to analyze the malignant progression of IDH1-mutant gliomas. They observe nonlinear clonal expansion of the original tumors and identify oncogenic pathways driving progression, including activation of MYC and RTK-RAS-PI3K pathways and epigenetic silencing of developmental transcription factors.

Paul Khavari and colleagues analyze tumor genomes to identify snoRNAs showing frequent copy number loss of adjacently encoded snoRNAs SNORD50A and SNORD50B. These snoRNAs directly bound K-Ras and their loss leads to increased activity of both wild-type and oncogenic K-Ras and is associated with reduced survival.

Andrew Jackson, Grant Stewart, Bernd Wollnik and colleagues identify TRAIP mutations in three patients with primordial dwarfism. They show that TRAIP is involved in DNA damage response during genome replication and is necessary for efficient cell cycle progression.

Renee Reijo Pera, Vittorio Sebastiano and colleagues identify three human pluripotency-associated transcripts (HPATs) that function in preimplantation development. They find that these three HPATs are also required for efficient nuclear reprogramming and that one, HPAT5, interacts with let-7 to modulate gene expression during reprogramming and differentiation.

Terry Burke, Mark Blaxter, David Lank and colleagues report a reference genome sequence of the ruff and analysis of the three distinct male morphs of this bird species. They identify a ‘supergene’ consisting of a fixed inversion in two of the morphs and identify candidate reproductive trait genes in this region.

José M. Jiménez-Gómez and colleagues report that the circadian clock of cultivated tomato was quantitatively slowed during domestication compared to its wild relatives, based on measurements of circadian leaf movements. They map QTL for phase and period, and identify the causal gene, EID1, underlying the phase QTL.