Variation in genome structure is an important source of human genetic polymorphism: It affects a large proportion of the genome and has a variety of phenotypic consequences relevant to health and disease. In spite of this, human genome structure variation is incompletely characterized due to a lack of approaches for discovering a broad range of structural variants in a global, comprehensive fashion. We addressed this gap with Optical Mapping, a highthroughput, high-resolution single-molecule system for studying genome structure. We used Optical Mapping to create genomewide restriction maps of a complete hydatidiform mole and three lymphoblast-derived cell lines, and we validated the approach by demonstrating a strong concordance with existing methods. We also describe thousands of new variants with sizes ranging from kb to Mb. structural variation | copy number variation | optical mapping | single-molecule genomics | genome assembly R ecent reports (1-11) have firmly established genome structural variation as an important and pervasive source of genetic polymorphism. Since the initial reports (1, 2) of widespread copy-number variation between the genomes of phenotypically normal individuals, investigators have applied hybridizationbased methods (3, 7, 9, 11), computational approaches (5, 6), clone paired-end sequencing (4, 10) and most recently a pairedend sequencing by synthesis approach (8) to the discovery and characterization of structural polymorphism. Others have described phenotypic consequences of these variants, including associations with myocardial infarction, neuroblastoma, autism, and schizophrenia (reviewed recently in ref. 12). Finally, their consistent association with segmental duplications and other classes of repeats (13) provides a mechanistic explanation for their origin (14) and points to a previously unappreciated role in evolution (15) as well as disease.Unfortunately, despite all efforts, a comprehensive picture of genome structure polymorphism has not yet emerged. Current genome-wide studies of structural variation manifest only modest concordance, possibly due to ascertainment biases arising from the techniques employed. For example, hybridization-based methods (2,3,7,9,11,16) are subject to nonspecific hybridization in repeat-rich regions, while clone-based strategies (4,8,10) are limited by maximum clone insert sizes and a wide clone size distribution relative to the events they are trying to detect. More recently, several entire human genomes were sequenced using high-throughput methods (17)(18)(19)(20), but the difficulty of interrogating repeat-rich regions is compounded by these systems' short read lengths.In an effort to overcome these challenges, we have applied Optical Mapping to the problem of discerning structural variation in normal human genomes. Optical Mapping (21-35) is a highthroughput system that combines single-molecule measurements with dedicated computational analysis to produce ordered restriction maps from individual molecules of genomic DNA: essentially, a singl...
Rhodospirillum rubrum is a phototrophic purple nonsulfur bacterium known for its unique and well-studied nitrogen fixation and carbon monoxide oxidation systems and as a source of hydrogen and biodegradable plastic production. To better understand this organism and to facilitate assembly of its sequence, three whole-genome restriction endonuclease maps (XbaI, NheI, and HindIII) of R. rubrum strain ATCC 11170 were created by optical mapping. Optical mapping is a system for creating whole-genome ordered restriction endonuclease maps from randomly sheared genomic DNA molecules extracted from cells. During the sequence finishing process, all three optical maps confirmed a putative error in sequence assembly, while the HindIII map acted as a scaffold for high-resolution alignment with sequence contigs spanning the whole genome. In addition to highlighting optical mapping's role in the assembly and confirmation of genome sequence, this work underscores the unique niche in resolution occupied by the optical mapping system. With a resolution ranging from 6.5 kb (previously published) to 45 kb (reported here), optical mapping advances a "molecular cytogenetics" approach to solving problems in genomic analysis.
Rhodospirillum rubrum (Esmarch 1887) Molisch 1907 is the type species of the genus Rhodospirillum, which is the type genus of the family Rhodospirillaceae in the class Alphaproteobacteria. The species is of special interest because it is an anoxygenic phototroph that produces extracellular elemental sulfur (instead of oxygen) while harvesting light. It contains one of the most simple photosynthetic systems currently known, lacking light harvesting complex 2. Strain S1T can grow on carbon monoxide as sole energy source. With currently over 1,750 PubMed entries, R. rubrum is one of the most intensively studied microbial species, in particular for physiological and genetic studies. Next to R. centenum strain SW, the genome sequence of strain S1T is only the second genome of a member of the genus Rhodospirillum to be published, but the first type strain genome from the genus. The 4,352,825 bp long chromosome and 53,732 bp plasmid with a total of 3,850 protein-coding and 83 RNA genes were sequenced as part of the DOE Joint Genome Institute Program DOEM 2002.
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