Unknown,Transcriptomics,Genomics,Proteomics

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Fine-Scale Mapping and Sequencing of Structural Variation from Eight Human Genomes

ABSTRACT: Genetic variation amongst individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single-nucleotide changes. In this manuscript we explore variation on an intermediate scale-particularly insertions, deletions, and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number among individuals. Sequencing of a subset of structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence-map of human structural variation-an important standard for genotyping platforms and a prelude to future individual genome sequencing projects. Keywords: comparative genomic hybridization The DNA samples are a panel of 8 Hapmap samples, described by E. Eichler et al. (2007, Nature 447, 161-165). This set of 7 female, and one male samples are from from the Coriell Cell Repository, and is comprised of samples from four populations: four Yoruban, two CEPH, one Chinese, and one Japanese. The reference sample, NA15510, is female and also from the Corriel Cell Repository. This sample has been extensively characterized, (for example in Tuzan et al. 2005, Nature Genetics 10, p1038) and has been recommended for use in CNV detection programs to allow meaningful comparison of data between studies (discussed in Scherer, et al. 2007, Nature Genetics Supplement 39: S7-S15). Each of these samples was hybridized in pairs with the reversed labeling polarities. Additionally, 3 self-self control hybridizations were carried out for the reference sample, NA15510, one on each hybridization date.

ORGANISM(S): Homo sapiens

SUBMITTER: Lin Chen

PROVIDER: E-GEOD-10008 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Mapping and sequencing of structural variation from eight human genomes.

Kidd Jeffrey M JM Cooper Gregory M GM Donahue William F WF Hayden Hillary S HS Sampas Nick N Graves Tina T Hansen Nancy N Teague Brian B Alkan Can C Antonacci Francesca F Haugen Eric E Zerr Troy T Yamada N Alice NA Tsang Peter P Newman Tera L TL Tüzün Eray E Cheng Ze Z Ebling Heather M HM Tusneem Nadeem N David Robert R Gillett Will W Phelps Karen A KA Weaver Molly M Saranga David D Brand Adrianne A Tao Wei W Gustafson Erik E McKernan Kevin K Chen Lin L Malig Maika M Smith Joshua D JD Korn Joshua M JM McCarroll Steven A SA Altshuler David A DA Peiffer Daniel A DA Dorschner Michael M Stamatoyannopoulos John J Schwartz David D Nickerson Deborah A DA Mullikin James C JC Wilson Richard K RK Bruhn Laurakay L Olson Maynard V MV Kaul Rajinder R Smith Douglas R DR Eichler Evan E EE

Nature 20080501 7191

Genetic variation among individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single nucleotide changes. Here we explore variation on an intermediate scale--particularly insertions, deletions and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive ov ...[more]

PMID: 18451855

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Project description:Despite considerable excitement over the potential functional significance of copy number variants (CNVs), we still lack knowledge of the fine-scale architecture of the large majority of CNV regions in the human genome. In this study, we used a high-resolution array-based comparative genomic hybridization (aCGH) platform that targeted known CNV regions of the human genome at ~1 kb resolution to interrogate the genomic DNAs of 30 individuals from four HapMap populations. Our results revealed that 1,020 of 1,153 CNV loci (88%) were actually smaller in size than what is recorded in the Database of Genomic Variants based on previously published studies. A reduction in size of more than 50% was observed for 876 CNV regions (76%). We conclude that the total genomic content of common human CNVs may be smaller than previously thought. In addition, approximately 8% of the CNV regions observed in multiple individuals exhibited genomic architectural complexity in the form of smaller CNVs within larger ones and CNVs with inter-individual variation in breakpoints. Future association studies that aim to capture the potential influences of CNVs on disease phenotypes will need to consider how to best ascertain this previously underappreciated complexity. The DNA samples are a panel of 30 Hapmap samples, and a female sample NA15510 of undetermined geographic origin, which has been well characterized by fosmid-end sequencing (Tuzun et al. 2005, Nature Genetics 10, p1038). The DNA for this set of 16 female and 15 male samples are all supplied by the Coriell Cell Repository, and is comprised of samples from four populations: 10 unrelated Yoruban, 10 unrelated European-American individuals from Utah (CEPH), 5 unrelated Chinese, and 5 unrelated Japanese. The reference sample, NA10851 is also a male CEPH also from the HapMap Sample set (Corriel Cell Repository). Each of these samples was hybridized in pairs with the reversed labeling polarities. Additionally, 3 self-self control hybridizations were carried out for the reference sample, NA10851, one on each hybridization date. In the Title for each of the samples, each hybridization session is indicated by the letters A, B or C.

Dataset Information

Fine-Scale Mapping and Sequencing of Structural Variation from Eight Human Genomes

Publications

Mapping and sequencing of structural variation from eight human genomes.

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