Unraveling the genetic control of diseases has important impact in disease prevention, diagnosis and therapy. Positional cloning is the main strategy for disease gene mapping. Despite advances in technology and increasing resources such as semi-automated genotyping instruments and dense maps of genetic markers, gene mapping remains a difficult task. Recently, we have developed an alternative gene mapping method that does not require genotyping. Instead gene regions are isolated by genome screens for shared genomic segments between individuals affected with the disease of interest. The isolated DNA fragments are then mapped by hybridization onto a genomic microarray. We call this method direct identical by descent (IBD) mapping. It is a combination of two techniques: genomic mismatch scanning and DNA microarrays. We have shown that direct IBD mapping is feasible on one chromosome by mapping the gene for congenital hyperinsulinism. The goal of this proposal is to expand this result by accomplishing the following aims. 1. To generate a whole genome DNA microarray for gene mapping, a """"""""genome on a chip"""""""". 2. To test genome wide IBD mapping in CEPH grandparent-grandchild pairs. 3. To develop statistical methods for the analysis of data derived from direct IBD mapping. Development of direct IBD mapping should provide a gene mapping method that is less labor-intensive and more efficient than the current methods. We expect that it can be applied as a tool for genome wide linkage disequilibrium analysis and affected relative pair mapping.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
1R01HG001880-01
Application #
2743146
Study Section
Genome Study Section (GNM)
Program Officer
Brooks, Lisa
Project Start
1999-01-01
Project End
2003-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Cheung, Vivian G; Sherman, Stephanie L; Feingold, Eleanor (2010) Genetics. Genetic control of hotspots. Science 327:791-2
Chowdhury, Reshmi; Bois, Philippe R J; Feingold, Eleanor et al. (2009) Genetic analysis of variation in human meiotic recombination. PLoS Genet 5:e1000648
Oliver, Tiffany Renee; Feingold, Eleanor; Yu, Kai et al. (2008) New insights into human nondisjunction of chromosome 21 in oocytes. PLoS Genet 4:e1000033
Cheung, Vivian G; Burdick, Joshua T; Hirschmann, Deborah et al. (2007) Polymorphic variation in human meiotic recombination. Am J Hum Genet 80:526-30
Bruzel, Alan; Cheung, Vivian G (2006) DNA reassociation using oscillating phenol emulsions. Genomics 87:286-9
Smirnov, Denis A; Burdick, Josh T; Morley, Michael et al. (2004) Method for manufacturing whole-genome microarrays by rolling circle amplification. Genes Chromosomes Cancer 40:72-7
Smirnov, Denis; Bruzel, Alan; Morley, Michael et al. (2004) Direct IBD mapping: identical-by-descent mapping without genotyping. Genomics 83:335-45
Cheung, V G; Jen, K Y; Weber, T et al. (2003) Genetics of quantitative variation in human gene expression. Cold Spring Harb Symp Quant Biol 68:403-7
Morley, M; Arcaro, M; Burdick, J et al. (2001) GenMapDB: a database of mapped human BAC clones. Nucleic Acids Res 29:144-7
Cheung, V G; Dalrymple, H L; Narasimhan, S et al. (1999) A resource of mapped human bacterial artificial chromosome clones. Genome Res 9:989-93