Segmental Duplications in Neurodevelopmental, Neurological and Behavioural Disorders
Websites:
Human Segmental Duplication Database: http://projects.tcag.ca/humandup/
Non-Human Segmental Duplication Database: http://projects.tcag.ca/xenodup/
Database of Genomics Variants: http://projects.tcag.ca/variation/
Summary
Genetic defects contribute to many neurodevelopmental and behavioural diseases, but in most cases scientists have not yet uncovered the causative molecular defect. As a result there are no tests for early detection and diagnosis of these disorders and little information about their biological basis. We are learning, however, that such conditions result from changes in the architecture of specific sites along the DNA of chromosomes in the human genome, so-called 'chromosome alterations'.
The human genome sequence has revealed the importance of such chromosome alterations. We now know that the sequence harbours ‘molecular signatures’ that facilitate rearrangements of genomic material. Furthermore, individuals and species vary in their genomic structure and the copy number of genes at specific regions of the genome, which in turn seem to influence evolution.
This project, funded by Genome Canada/OGI in partnership with Genoma España, resulted in numerous high-impact publications on the subject of genomic structural variation and CNV detection methodologies (see ‘Notable Publications’, below). It also contributed significantly to the sequencing of the first individual diploid human genome (see Levy et al, 2007, below). This project also created a number of important genomics resources, most notably the Database of Genomic Variants (DGV – see link above), which continues to accumulate new variant entries and attract thousands of users each year.
Principal investigators on this project included scientific research groups from the University of Toronto, the University of British Columbia, SeeDNA Biotech, Fundacio Parc de Recera Ciomedica de Barcelona, Universidad Pompeu Fabra, MedPlant Genetics (Spain), and CAGT-Citogen (Spain).
Notable Publications
Scherer SW, et al. 2007. Challenges and standards in integrating surveys of structural variation. Nat Genet. 39 (7 Suppl): S7-15.
Levy S, et al. 2007. The diploid genome sequence of an individual human. PLoS Biol. 5(10): e254.
Stranger BE, Forrest MS, Dunning M, Ingle CE, Beazley C, Thorne N, Redon R, Bird CP, de Grassi A, Lee C, Tyler-Smith C, Carter N, Scherer SW, Tavare S, Deloukas P, Hurles ME, and Dermitzakis ET. 2007. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science, 315: 848-53.
Redon R, et al. 2006. Global variation in copy number in the human genome. Nature 444(7118): 444-54.
Feuk L, Carson AR, and Scherer SW. 2006. Structural variation in the human genome. NatRev Genet. 7: 85-97.
Somerville MJ, Mervis CB, Young EJ, Seo E-J, del Campo M, Bamforth JS, Peregrine E, Loo W, Lilley M, Perez-Jurado LA, Morris CA, Scherer SW and Osborne LR. 2005. Severe expressive-language delay related to duplication of the Williams-Beuren Locus. N Eng J Med. 353: 1694-1701.
