We will apply next-generation sequencing (NGS) technology to assess the genome-wide pattern of structural variation within large (>20 kbp), complex regions of segmental duplication. Combining read-depth and a single-base unique nucleotide (SUN) identifier map, we will generate absolute estimates of diploid copy-number and sequence content for duplicated regions and gene families. We propose to analyze all 2,000 individuals being analyzed as part of the 1000 Genomes Project and to validate regions by a combination of array comparative genomic hybridization (arrayCGH), clone-based sequencing and FISH-based approaches.
This aim will provide the first genotypic assessment of copy and content of these complex regions facilitating future disease association studies.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Program Projects (P01)
Project #
5P01HG004120-07
Application #
8489317
Study Section
Ethical, Legal, Social Implications Review Committee (GNOM)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
7
Fiscal Year
2013
Total Cost
$362,283
Indirect Cost
$130,049
Name
University of Washington
Department
Type
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Antonacci, Francesca; Dennis, Megan Y; Huddleston, John et al. (2014) Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability. Nat Genet 46:1293-302
Lazaridis, Iosif; Patterson, Nick; Mittnik, Alissa et al. (2014) Ancient human genomes suggest three ancestral populations for present-day Europeans. Nature 513:409-13
Nuttle, Xander; Itsara, Andy; Shendure, Jay et al. (2014) Resolving genomic disorder-associated breakpoints within segmental DNA duplications using massively parallel sequencing. Nat Protoc 9:1496-513
Mueller, Michael; Barros, Paula; Witherden, Abigail S et al. (2013) Genomic pathology of SLE-associated copy-number variation at the FCGR2C/FCGR3B/FCGR2B locus. Am J Hum Genet 92:28-40
Watson, Corey T; Steinberg, Karyn M; Huddleston, John et al. (2013) Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation. Am J Hum Genet 92:530-46
Nuttle, Xander; Huddleston, John; O'Roak, Brian J et al. (2013) Rapid and accurate large-scale genotyping of duplicated genes and discovery of interlocus gene conversions. Nat Methods 10:903-9

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