Abstract

The overall aim of this project is to define the evolutionary origins of local, low-order repeated sequences that contribute to genetic diseases in humans. This project will contribute materials and expertise to project I- III and assist with characterization of sequences under study in the laboratories of Drs. Morrow, Lupski and Shaffer. In addition, this project will carry out analysis of regions of the human X chromosome that carry out similar sequences involved in genetic disease. This effort will be carried out in conjunction with a project to define the molecular breakpoint of chromosomal rearrangements that have occurred among the great apes. The data developed in this project will lead to a greater understanding of the origin of sequence subject to instability in disease. Furthermore, understanding the molecular causes and effects of genome change may lead to greater insight into the evolutionary process.
Four specific aims are proposed: 1. Characterize the LCR22 from chromosome 22 in higher primates to determine their evolutionary origins. 2. Analyze the region-specific low-copy repeat gene clusters in proximal human chromosome 17 and determine their evolutionary origins. 3. Determine the subtoleromeric DNA structures on distal human 1p and analyze their structures and chromosomal distribution among the great apes. 4. Determine the evolutionary origin of two local repeats on the human X chromosome-those involved in deletions of Xp22.3 leading to steroid sulfatase deficiency and those involved in Xq28 inversions resulting in Hemophilia A. Successful completion of these aims will refine hypotheses regarding the mechanisms responsible for generating the sequences that lead to high frequency rearrangements associated with human genetic disease. It is anticipated that understanding the features involved in these regions will help to predict additional region subject to similar changes. This will in turn lead to recognition of the molecular basis for mental retardation and development of refined diagnostic assays.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD039420-01A1
Application #
6475463
Study Section
Special Emphasis Panel (ZHD1)
Project Start
2001-06-11
Project End
2006-05-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Alkalay, Avishai A; Guo, Tingwei; Montagna, Cristina et al. (2011) Genetic dosage compensation in a family with velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome. Am J Med Genet A 155A:548-54
Yatsenko, Svetlana A; Brundage, Ellen K; Roney, Erin K et al. (2009) Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome. Hum Mol Genet 18:1924-36
Yan, J; Zhang, F; Brundage, E et al. (2009) Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange. J Med Genet 46:626-34
Bi, Weimin; Sapir, Tamar; Shchelochkov, Oleg A et al. (2009) Increased LIS1 expression affects human and mouse brain development. Nat Genet 41:168-77
Dobyns, William B; Mirzaa, Ghayda; Christian, Susan L et al. (2008) Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36.3, 2p16.1-p23.1, 4q21.21-q22.1, 6q26-q27, and 21q2. Am J Med Genet A 146A:1637-54
Carvalho, Claudia M B; Lupski, James R (2008) Copy number variation at the breakpoint region of isochromosome 17q. Genome Res 18:1724-32
Borg, Katarzyna; Nowakowska, Beata; Obersztyn, Ewa et al. (2007) Complex balanced translocation t(1;5;7)(p32.1;q14.3;p21.3) and two microdeletions del(1)(p31.1p31.1) and del(7)(p14.1p14.1) in a patient with features of Greig cephalopolysyndactyly and mental retardation. Am J Med Genet A 143A:2738-43
Simovich, Marcia J; Yatsenko, Svetlana A; Kang, Sung-Hae L et al. (2007) Prenatal diagnosis of a 9q34.3 microdeletion by array-CGH in a fetus with an apparently balanced translocation. Prenat Diagn 27:1112-7
Potocki, Lorraine; Bi, Weimin; Treadwell-Deering, Diane et al. (2007) Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 80:633-49
Babcock, Melanie; Yatsenko, Svetlana; Hopkins, Janet et al. (2007) Hominoid lineage specific amplification of low-copy repeats on 22q11.2 (LCR22s) associated with velo-cardio-facial/digeorge syndrome. Hum Mol Genet 16:2560-71

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