Rice, one of the world's most important food plants, has important syntenic relationships with the other cereal species and is a model plant for the grasses. Here we present a map-based, finished quality sequence that covers 95% of the 389 Mb genome, including virtually all of the euchromatin and two complete centromeres. A total of 37,544 nontransposable-element-related protein-coding genes were identified, of which 71% had a putative homologue in Arabidopsis. In a reciprocal analysis, 90% of the Arabidopsis proteins had a putative homologue in the predicted rice proteome. Twenty-nine per cent of the 37,544 predicted genes appear in clustered gene families. The number and classes of transposable elements found in the rice genome are consistent with the expansion of syntenic regions in the maize and sorghum genomes. We find evidence for widespread and recurrent gene transfer from the organelles to the nuclear chromosomes. The map-based sequence has proven useful for the identification of genes underlying agronomic traits. The additional single-nucleotide polymorphisms and simple sequence repeats identified in our study should accelerate improvements in rice production.

Rice, the primary source of dietary calories for half of humanity, is the first crop plant for which a high-quality reference genome sequence from a single variety was produced. We used resequencing microarrays to interrogate 100 Mb of the unique fraction of the reference genome for 20 diverse varieties and landraces that capture the impressive genotypic and phenotypic diversity of domesticated rice. Here, we report the distribution of 160,000 nonredundant SNPs. Introgression patterns of shared SNPs revealed the breeding history and relationships among the 20 varieties; some introgressed regions are associated with agronomic traits that mark major milestones in rice improvement. These comprehensive SNP data provide a foundation for deep exploration of rice diversity and gene-trait relationships and their use for future rice improvement.introgression ͉ Oryza sativa ͉ resequencing ͉ SNP discovery T he genomes of domesticated rice, Oryza sativa, contain a wealth of information that can explain the large morphological, physiological, and ecological variation observed in the many varieties cultivated for food. To meet population demands by 2025, rice production must increase by 24% (1). The innovative use of genetic diversity will play a key role in reaching this ambitious goal.The availability of complete genome sequences provides a starting point to understanding the tremendous diversity of the rice gene pool at a fine scale. Among the organisms with a high-quality genome sequence from at least one individual or strain, such as human, mouse, and Arabidopsis, genomewide surveys of SNP variation in small or moderately sized samples have captured significant portions of within-species variation. In human and mouse, for example, a sampling of 71 and 15 individuals captured 80% and 43% of the genotypic variation, respectively (2, 3). In the model plant, Arabidopsis, 20 diverse varieties captured Ͼ90% of the common genotypic variation in the species (4).We initiated the OryzaSNP project (www.OryzaSNP.org) to discover genetic variation within 20 rice varieties and landraces. These varieties, the OryzaSNPset collection (Table S1), are genetically diverse and actively used in international breeding programs because of their wide range of agronomic attributes (5). Most varieties belong to the 2 main groups, indica and japonica, including tropical and temperate japonica, whereas others represent the aus, deep water, and aromatic rice groups. Adapting a hybridization approach previously used for human, mouse, and Arabidopsis (3, 6, 7), we determined SNP variation in 100 Mb of the rice genome, representing Ϸ80% of the nonrepetitive portion of the 390-Mb Nipponbare reference genome (8). Here, we describe the discovery of 159,478 high-quality, nonredundant SNPs distributed across the entire genomes of the OryzaSNPset. Relative to the model dicotyledenous plant Arabidopsis (4), typical haplotype blocks in indica rice varieties are longer (Ϸ200 kb). Observed patterns of shared SNPs among groups indicate introgression caused by rece...

Despite the central importance of noncoding DNA to gene regulation and evolution, understanding of the extent of selection on plant noncoding DNA remains limited compared to that of other organisms. Here we report sequencing of genomes from three Brassicaceae species (Leavenworthia alabamica, Sisymbrium irio and Aethionema arabicum) and their joint analysis with six previously sequenced crucifer genomes. Conservation across orthologous bases suggests that at least 17% of the Arabidopsis thaliana genome is under selection, with nearly one-quarter of the sequence under selection lying outside of coding regions. Much of this sequence can be localized to approximately 90,000 conserved noncoding sequences (CNSs) that show evidence of transcriptional and post-transcriptional regulation. Population genomics analyses of two crucifer species, A. thaliana and Capsella grandiflora, confirm that most of the identified CNSs are evolving under medium to strong purifying selection. Overall, these CNSs highlight both similarities and several key differences between the regulatory DNA of plants and other species.

Anti-tumor immunity is driven by self vs. non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole genome sequencing (WGS) and RNA sequencing (RNA-seq), we identified a novel gene fusion, and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration, and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens, and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.