Structural variation (ESHG 2008 abstracts)

European Human Genetics Conference (abstract database)

Genomic structural variation profiles of world human populations

Presentation Time: Saturday, 7:30 p.m. - 7:45 p.m.
L. Bassaganyas1,2,3, M. Garcia1,3, M. Montfort1,4,3, L. Armengol1,3, X. Estivill1,4,3;
1Center for Genomic Regulation (CRG), Barcelona, Catalonia, Spain, 2Pompeu Fabra University (UPF), Barcelona, Catalonia, Spain, 3Public Health and Epidemiology Network Biomedical Research Center (CIBERESP), Barcelona, Catalonia, Spain, 4National Genotyping Center (CeGen), Barcelona, Catalonia, Spain.
Presentation Number: PL2.5
Genomic variants can contribute to genetic disease, and are potential substrates for natural selection resulting in phenotypic differences between individuals. The use of genome-wide molecular methods have revealed the existence of Copy Number Variants (CNVs), genomic segments ranging in size from one kb to several megabases, that are present at variable copy number in comparison with a reference genome. The aim of our study was to determine the existence of population-specific genomic structural variation and to identify genes located in these regions that might contribute to phenotypic differences as well as to differential susceptibility to common disease and environmental exposures of human populations. We have selected 343 individuals from 11 populations from the HGDP-CEPH panel (Biaka- Mbuti Pygmy, Bantu, Mozabite, Bedouin, Brahui, Hazara, Yakut, Papuan-Melanesian, French, Pima and Maya) and 134 individuals from the three populations of the HapMap collection (YRI, CHB and CEU). To detect structural variation we have used array-CGH (Agilent 244K) and array-based comparative genome intensity (Illumina). We have observed differences between populations in 179 loci. 122 of these were already described in the Database of Genomic Variants and 58 coincide with segmental duplications. Interestingly, a number of genes involved in different common disorders or to have phenotypic differences between population groups were found to be variable in copy number among human populations (i.e. RHD, CFHR1, CFHR3 and PRSS1). These loci and others could explain differences in disease predisposition among individuals from different populations and could provide important clues on the adaptation of humans to different environments.

A full survey of common copy number variation in the human genome
Presentation Time: Tuesday, 11:15 a.m. - 11:30 a.m.
R. Redon1, D. F. Conrad1, L. Feuk2, C. Lee3, S. W. Scherer2, M. E. Hurles1, N. P. Carter1;
1Wellcome Trust Sanger Institute, Cambridge, United Kingdom, 2The Hospital for Sick Children, Toronto, ON, Canada, 3Brigham and Women’s Hospital, Boston, MA, United States.
Presentation Number: C13.3
Copy number variation (CNV) in the genome is extensive and yet is grossly under-ascertained. As smaller CNVs are expected to be far more numerous than larger CNVs, improved CNV detection resolution will dramatically increase the numbers of known CNVs. The Genome Structural Variation Consortium has performed comparative genome hybridisation on a genome-wide set of tiling oligonucleotide arrays to discover the majority of common copy number variants >500bp in size in two populations with African and European ancestry. This set covers the assayable portion of the human genome with 42,000,000 probes with a median spacing of ~50bp. In addition we have generated data on a single chimpanzee to provide information on the ancestral state of observed variants. The results reveal, as expected, that previous surveys captured only 5-10% of the CNVs within a single genome. Because the boundaries of thousands of CNVs are defined precisely by this probe set, we can identify accurately functional sequences included in copy number variable regions. This provides new insights into the mechanisms generating chromosomal rearrangements and the biological functions of common CNVs.

A high-resolution structural variation map of a human genome by next-generation, high-throughput paired-end sequencing
Presentation Time: Sunday, 3:15 p.m. - 3:30 p.m.
F. M. De La Vega1, H. E. Peckham2, S. S. Ranade2, S. F. McLaughlin2, C. C. Lee2, Y. Fu2, Z. Zhang1, F. C. L. Hyland1, C. L. Clouser2, A. A. Antipova2, J. M. Manning2, C. L. Hendrickson2, L. Zhang2, E. T. Dimalanta2, T. D. Sokolsky2, M. W. Laptewicz2, B. E. Coleman2, J. K. Ichikawa2, J. B. Warner2, B. Li1, J. M. Kidd3, J. A. Malek4, G. L. Costa2, E. E. Eichler3, K. J. McKernan2;
1Applied Biosystems, Foster City, CA, United States, 2Applied Biosystems, Beverly, MA, United States, 3HHMI, University of Washington, Seattle, WA, United States, 4Weill Cornell Medical College in Qatar, Doha, Qatar.
Presentation Number: C05.2
The human genome and HapMap projects have considerably increased our understanding of the role of sequence variation in evolution and disease. Hybridization microarrays and fosmid-end sequencing reveal that structural variants (SVs) including insertions, deletions, duplications, inversions and translocations are common and extensive. Microarray methods, however, lack resolution and are blind to unbalanced events, while clone-based end-sequencing is time consuming and expensive. Here, we present a high-resolution survey of SVs of a human genome, a HapMap Yoruba sample (NA18507), by ultra-high throughput sequencing of paired-end libraries with the AB SOLiD(TM) System. We sequenced a variety of 2x25-bp paired-end libraries (>15Gb) with insert sizes ranging from 600bp to 6kb (SD 10-23%). Each library provides over 10x physical (clone) coverage, with a total combined physical coverage >60x for 90% of the genome. The high physical coverage and diverse insert sizes allowed detecting small indels within tags (1-10 bp), and approximately 70,000 indels of length 20 bp to >100 kb. Additionally, we sequenced 7Gb of 50-bp fragment libraries, which combined with the paired libraries provided over 12x sequence coverage, allowing us to discover millions of SNPs of which 75% are found in dbSNP. Inferred SVs were compared to a database of end-sequence pairs of 10x physical coverage obtained by di-deoxy sequencing of 40kb fosmid ends. A subset of novel SVs were validated by PCR and Sanger sequencing. Our results serves as a model for further high-resolution exploration of genetic variation in human populations and cancer with next-generation sequencing.

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