Articles in 2015

Large sample sizes, high-resolution arrays and comprehensive imputation are pushing genetic fine-mapping of complex trait loci to its limits without, in most cases, pinpointing a unique variant-gene combination. Superimposing these results on sophisticated maps of functional chromatin elements promises to break this logjam, as a new study of type 2 diabetes compellingly demonstrates.

The genome sequence assembly of the highly heterozygous Ananas comosus and its varieties is an impressive technical achievement. The sequence opens the door to a greater understanding of pineapple morphology and evolution.

Carrolee Barlow, J. William Langston, Birgitt Schüle and colleagues review the current classification of parkinsonian disorders. They propose the term 'multisystem Lewy body disease' to encompass three genetic subtypes of Parkinson's disease and distinguish this from other non–Lewy body parkinsonian disorders.

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.

Leif Andersson and colleagues report the genome sequence of the ruff, a bird species with three male morphs with different reproductive strategies. Satellite and faeder morphs differ from the common independent morph by a 4.5-Mb inversion that occurred approximately 3.8 million years ago, and multiple genetic changes within this inverted region are associated with the satellite and faeder morphs.

Christopher Haiman, Bogdan Pasaniuc, David Reich and colleagues report a major role for low-frequency variation in the risk for prostate cancer. They show that alleles with >1% minor allele frequency contribute an order of magnitude more to risk for prostate cancer than these alleles do to overall genetic variation.

Kyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk.

Ludmil Alexandrov, Michael Stratton and colleagues analyze 10,250 human cancer genomes from 36 cancer types to identify mutational signatures with clock-like properties. They identify two signatures with different mutation rates that show a correlation between age at diagnosis and number of mutations in most cancer types.

Evans Lagudah and colleagues report that variation in a gene encoding a hexose transporter confers resistance to multiple pathogens in wheat. They further show that the variant protein encoded by the resistance allele exerts a dominant-negative effect by heterodimerizing with functional hexose transporters, resulting in reduced glucose uptake.

Nazneen Rahman and colleagues identify inactivating germline mutations in the gene encoding the transcriptional repressor REST in familial and non-familial cases of Wilms tumor. The mutations cluster in the DNA-binding domain of REST and compromise REST transcriptional repression.

Teresa Palomero, Adolfo Ferrando, Raul Rabadan and colleagues report the results of an exome sequencing study of cutaneous T cell lymphoma (CTCL). They identify highly recurrent chromosomal deletions along with a broad spectrum of somatic mutations in genes involved in epigenetic regulation and signaling.

Madeleine Duvic, David Wheeler and colleagues present an integrated genomic analysis of Sézary syndrome. They identify recurrent alterations in key T cell signaling and differentiation genes and observe overexpression of IL32 and IL2RG in nearly all cases.

Rogier Versteeg and colleagues analyze the whole-genome sequences of 108 neuroblastoma samples and detect structural rearrangements of TERT in 23% of high-stage cases. TERT rearrangements are associated with increased TERT expression, increased telomere length and very poor prognosis.