Cytosine DNA methylation is important in regulating gene expression and in silencing transposons and other repetitive sequences 1, 2 . Recent genomic studies in Arabidopsis have revealed that many endogenous genes are methylated either within their promoters or within their transcribed regions, and that gene methylation is highly correlated with transcription levels 3-5 . However, plants have different types of methylation controlled by different genetic pathways, and detailed information on the methylation status of each cytosine in any given genome is lacking. To this end, we generated a map at single base pair resolution of methylated cytosines for Arabidopsis, by combining bisulfite treatment of genomic DNA with ultra-high-throughput sequencing using the Illumina 1G Genome Analyzer and Solexa sequencing technology 6 . This approach, termed BS-Seq, unlike previous microarray-based methods, allows one to sensitively measure cytosine methylation on a genomewide scale within specific sequence contexts. We describe methylation on previously inaccessible components of the genome along with an analysis of the DNA methylation sequence composition and distribution. We also describe the effect of various DNA methylation mutants on genome-wide methylation patterns, and demonstrate that our newly developed library construction and computational methods can be applied to large genomes such as mouse.To generate a DNA methylation map at one nucleotide resolution across the genome, we adapted the Illumina 1G Genome Analyzer using Solexa sequencing technology (Illumina GA) for shotgun sequencing of bisulfite-treated Arabidopsis genomic DNA. Sodium bisulfite converts unmethylated cytosines to uracils, but 5-methylcytosines remain unconverted. Hence, Author Information. Reprints and permissions information is available at www.nature.com/reprints. The authors declare competing financial interests: details accompany the full-text HTML version of the paper at www.nature.com/nature. Correspondence and requests for materials should be addressed to S.E.J. (jacobsen@ucla.edu) or M.P. (matteop@mcdb.ucla.edu). 6 These authors contributed equally to this work. 7 Present address: Department of Plant Biology, University of Georgia, Athens, Georgia 30602, USA. Author Contributions. S.J.C. developed computational methods for mapping and basecalling. S.F. designed and created DNA libraries and performed all molecular biology experiments. S.F., Z.C., B.M., and S.F.N. sequenced libraries. M.P., S.J.C., S.F., and S.E.J. analyzed data. S.E.J. and M.P. designed and directed the study. X.Z., C.D.H., and S.P. assisted in the design of experiments. S.F. and S.J.C. wrote the manuscript. HHMI Author ManuscriptHHMI Author Manuscript HHMI Author Manuscript after polymerase chain reaction amplification, unmethylated cytosines appear as thymines and methylated cytosines appear as cytosines 7 . We created genomic DNA libraries after bisulfite conversion and produced ~3.8 billion nucleotides of high quality sequence which successfully mapped to the...

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kilobases were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.

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We develop a fast method to localize the level set method of Osher and Sethian (1988, J. Comput. Phys. 79, 12) and address two important issues that are intrinsic to the level set method: (a) how to extend a quantity that is given only on the interface to a neighborhood of the interface; (b) how to reset the level set function to be a signed distance function to the interface efficiently without appreciably moving the interface. This fast local level set method reduces the computational effort by one order of magnitude, works in as much generality as the original one, and is conceptually simple and easy to implement. Our approach differs from previous related works in that we extract all the information needed from the level set function (or functions in multiphase flow) and do not need to find explicitly the location of the interface in the space domain. The complexity of our method to do tasks such as extension and distance reinitialization is O(N ), where N is the number of points in space, not O(N log N ) as in works by , Proc. Nat. Acad. Sci. 93, 1591 and Helmsen and co-workers (1996, SPIE Microlithography IX, p. 253). This complexity estimation is also valid for quite general geometrically based front motion for our localized method.

Background-The optimal time for the initiation of antiretroviral therapy for asymptomatic patients with human immunodeficiency virus (HIV) infection is uncertain.

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