Volume 47 Issue 12, December 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.

Characterizations of durable resistance genes in crop plants are coming to the fore. A new study characterizing the wheat gene Lr67 shows that how a plant manages sugar transport affects the ability of a broad group of fungal pathogens to colonize their host.

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.

Po-Ru Loh, Alkes Price and colleagues developed a fast algorithm for multicomponent, multi-trait variance-components analysis and use it to analyze the genetic architectures of schizophrenia and nine complex diseases from the PGC and GERA cohorts. Their analyses support a largely polygenic architecture for schizophrenia and significant genetic correlations for several pairs of GERA diseases.

Matthew Maurano, John Stamatoyannopoulos and colleagues identify 64,597 allelically imbalanced SNPs that influence transcription factor occupancy in vivo. Using these data, they develop a general scoring method to identify regulatory variants likely to affect transcription factor occupancy in the human genome.

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.

Yardena Samuels and colleagues report the analysis of 501 melanoma exomes and the identification of RASA2 as a tumor-suppressor gene mutated in 5% of melanomas. RASA2 mutations led to increased RAS activation, and RASA2 loss was associated with shorter patient survival times.

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.

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.

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.

Ray Ming, Robert Paull, Qingyi Yu and colleagues report the genome sequences of two cultivated pineapple varieties and one wild pineapple relative. Their analysis supports the use of the pineapple as a reference genome for monocot comparative genomics and provides insight into the evolution of crassulacean acid metabolism photosynthesis.

Felix Stickel and colleagues report the results of a genome-wide association study of alcohol-related cirrhosis. They confirm PNPLA3 as a susceptibility locus and identify new association signals in MBOAT7 and TM6SF2.

Lavinia Paternoster and colleagues report the results of a large, multi-ancestry genome-wide association study of atopic dermatitis. They identify ten new susceptibility loci harboring candidate genes involved in innate host defense and T cell function.

Timothy Vyse and colleagues report the results of a large-scale association study of systemic lupus erythematosus (SLE). They identify ten new susceptibility loci and implicate aberrant regulation of innate and adaptive immunity genes in disease pathogenesis.

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.

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.

Lewis Cantley and colleagues report an integrated metabolic and transcriptomic study of non–small cell lung cancer (NSCLC) cell lines. They show that the activity of the serine/glycine biosynthetic pathway in NSCLC is highly heterogeneous and is regulated by NRF2 and that elevated expression of genes in this pathway confers poor prognosis in human NSCLC.

Suneet Agarwal and colleagues use somatic cells and induced pluripotent stem cells from patients with PARN mutations to show that PARN is required for the 3′-end maturation of the telomerase RNA component TERC. Their findings provide a mechanism linking PARN mutations to telomere diseases.

Davide Sosso and colleagues show that SWEET4 hexose transporters are essential for grain filling in both maize and rice, and were likely selected during domestication to enhance sugar import into the endosperm.

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.