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: comparitive genomic hybridization, copy number variation, structural variation, fosmid end sequencing CGH analysis targeted against sites identified by fosmid end sequencing. 8 HapMap samples (sources of libraries ABC7-ABC14) are hybed against NA15510 (source of fosmid library G248).

ORGANISM(S): Homo sapiens

SUBMITTER: Lin Chen

PROVIDER: E-GEOD-10037 | 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:We used aCGH data for detailed analysis of the natural killer gene complex (NKC) of multiple inbred strains, providing insight both into aCGH analysis of polymorphic gene clusters as well as structural information on the NKC itself. By unsupervised clustering analysis, the aCGH data can be precisely correlated with overall genome structural variation of the NKC as detected by RFLP variants in retrospective and prospective analyses. On a high resolution level, aCGH could be used to detect a small deletion within an NKC gene that is confined to only one mouse strain examined out of 22. The NKC region on mouse chromosome 6 is known to be an area with structural variation based on studies which reveal restriction fragment length polymorphic (RFLP) variants among inbred mouse strains. To verify predictive power of the unsupervised clustering algorithms, we prospectively collected aCGH data from two strains of mice (CBA/J, and NZW/LacJ) that were not among the original 20 strains (GEO accession # GSE10656) analyzed but represented strains whose Ly49 and Nkrp1 RFLP had been determined previously. We performed comparative genomic hybridization using a long-oligonucleotide array containing 2,149,887 probes evenly spaced across the reference genome with a median inter-probe spacing of 1,015 bases. Labeling, hybridization, washing, and array imaging were performed as previously described (PMID:18334530). To capture the variability along chromosome 6, the log2 signal ratios were organized into bins (a defined chromosome length in terms of bp). The entire chromosome was divided into consecutive bins, beginning with the position of the first probe. We used the variance of each bin to represent the variability along the chromosome. We performed two types of unsupervised clustering analysis of the log2 ratios of signal intensities of each probe (normalized). One is the non-hierarchical clustering using the partitioning among medoids (PAM) function as implemented in R's 'cluster' package. The other is the agglomerative hierarchical clustering based on the Euclidean distance. The average linkage method was used in clustering the strains as implemented in the hclust function in R's 'cluster' package.

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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