SUMMARY Despite recent insights into melanoma genetics, systematic surveys for driver mutations are challenged by an abundance of passenger mutations caused by carcinogenic ultraviolet (UV) light exposure. We developed a permutation-based framework to address this challenge, employing mutation data from intronic sequences to control for passenger mutational load on a per gene basis. Analysis of large-scale melanoma exome data by this approach discovered six novel melanoma genes (PPP6C, RAC1, SNX31, TACC1, STK19 and ARID2), three of which - RAC1, PPP6C and STK19 - harbored recurrent and potentially targetable mutations. Integration with chromosomal copy number data contextualized the landscape of driver mutations, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations. The landscape also clarified a mutational basis for RB and p53 pathway deregulation in this malignancy. Finally, the spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis.

Quinoa (Chenopodium quinoa Willd., 2n = 4x = 36) is a highly nutritious crop that is adapted to thrive in a wide range of agroecosystems. It was presumably first domesticated more than 7,000 years ago by pre-Columbian cultures and was known as the 'mother grain' of the Incan Empire 1 . Quinoa has adapted to the high plains of the Andean Altiplano (> 3,500 m above sea level), where it has developed tolerance to several abiotic stresses [2][3][4] . Quinoa has gained international attention because of the nutritional value of its seeds, which are gluten-free, have a low glycaemic index 5 , and contain an excellent balance of essential amino acids, fibre, lipids, carbohydrates, vitamins, and minerals 6 . Quinoa has the potential to provide a highly nutritious food source that can be grown on marginal lands not currently suitable for other major crops. This potential was recognized when the United Nations declared 2013 as the International Year of Quinoa, this being one of only three times a plant has received such a designation.Despite its agronomic potential, quinoa is still an underutilized crop 7 , with relatively few active breeding programs 8 . Breeding efforts to improve the crop for important agronomic traits are needed to expand quinoa production worldwide. To accelerate the improvement of quinoa, we present here the allotetraploid quinoa genome. We demonstrate the utility of the genome sequence by identifying a gene that probably regulates the presence of seed triterpenoid saponin content. Moreover, we sequenced the genomes of additional diploid and tetraploid Chenopodium species to characterize genetic diversity within the primary germplasm pool for quinoa and to understand sub-genome evolution in quinoa. Together, these resources provide the foundation for accelerating the genetic improvement of the crop, with the objective of enhancing global food security for a growing world population. Sequencing, assembly and annotationWe sequenced and assembled the genome of the coastal Chilean quinoa accession PI 614886 (BioSample accession code SAMN04338310) using single-molecule real-time (SMRT) sequencing technology from Pacific Biosciences (PacBio) and optical and chromosome-contact maps from BioNano Genomics 9 and Dovetail Genomics 10 . The assembly contains 3,486 scaffolds, with a scaffold N50 of 3.84 Mb and 90% of the assembled genome contained in 439 scaffolds (Table 1). The total assembly size of 1.39 gigabases (Gb) is similar to the reported size estimates of the quinoa genome (1.45-1.50 Gb (refs 11,12)). To combine scaffolds into pseudomolecules, an existing linkage map from quinoa 13 was integrated with two new linkage maps. The resulting map (Extended Data Fig. 1) of 6,403 unique markers spans a total length of 2,034 centimorgans (cM) and consists of 18 linkage groups (Supplementary Table 7), corresponding to the haploid chromosome number of quinoa. Pseudomolecules (hereafter referred to as chromosomes, which are numbered according to a previously published single-nucleotide polymorphism (SNP) linkage ...

Genome-wide sequencing, mRNA and miRNA expression, DNA copy number and methylation analyses were performed on 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors. In addition to genes previously implicated in Wilms tumors (WT1, CTNNB1, FAM123B, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), mutations were identified in genes not previously recognized as recurrently involved in Wilms tumors, the most frequent being BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A. DNA copy number changes resulted in recurrent 1q gain, MYCN amplification, LIN28B gain, and let-7a loss. Unexpected germline variants involved PALB2 and CHEK2. Integrated analyses support two major classes of genetic changes that preserve the progenitor state and/or interrupt normal development.

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