Birth Defects, Congenital Anomalies, Genetic Diseases, Neurological and Behavioral Disorders, Genome Architecture, Chromosomal Rearrangements, Genomic Instability and High-throughput Genomewide Technologies.
Key words: Genome, Chromosome, Rearrangement, Genetic Diseases, Duplication, Deletion, Translocation, Microarray, Computational Analysis, Copy Number Variation
Description of Research
The research in my laboratory focuses on genetic diseases that occur due to chromosomal rearrangements such as microdeletions, interstitial duplications, translocations and inversions. Diseases arising from such structural rearrangements have been designated ?genomic disorders? and are estimated to occur at a frequency of 0.7-1/1000 live births. These disorders can manifest in the form of multiple congenital anomalies (MCA), which are a significant cause of morbidity and mortality in children. Microdeletions and microduplications can give rise to altered copy number of several genes or may disrupt the integrity of a single gene, causing disease. A few of the better characterized genomic disorders include Prader-Willi (PWS; MIM # 176270) and Angelman syndromes (AS; MIM# 105830)) on 15q11-q13 Williams-Beuren syndrome (WBS; MIM # 194050) on 7q11.23, Smith-Magenis syndrome (SMS; MIM # 182290)/duplication 17p11.2 on 17p11.2 (Chen et al., 1997) and several rearrangements associated with 22q11 including DiGeorge and velocardiofacial syndromes (DGS/VCFS; MIM # 188400) and cat eye syndrome (CES; MIM # 115470). Recently, there has been an increasing awareness that the genomic restructuring that leads to the above disorders is caused by aberrant recombination occurring at segmental duplications. Segmental duplications (SDs) are a class of repetitive DNA elements in the human genome which have resulted from duplication of large segments of genomic DNA ranging in size from 10-500 kb. The duplicated segments share >90% (typically 96-98%) nucleotide sequence identity with each other. This high level of paralogy over large stretches of DNA can lead to aberrant recombination due to misalignment between non-allelic sequences on homologous chromosomes. These regions of genomic instability are expected to be major contributors to the burden of cytogenetic and sub-microscopic chromosomal abnormalities seen in a clinical setting.
It is very likely that many genomic disorders go undetected due to the limitations of current techniques used in clinical diagnostics. Towards this end, we have an ongoing study in collaboration with the Clinical Genetics Center at the Children's Hospital of Philadelphia to investigate the role of copy number alterations of genomic regions in children with multiple birth defects.We use genomewide analysis with high resolution, oligonucleotide microarrays to detect copy number variation in our patients with congenital anomalies of unknown etiology. Our approach has allowed us to detect clinically relevant, submicroscopic rearrangements which were missed by clinical tests. Most of the rearrangements identified are novel and involve several genes. Based on the multiorgan effects of the rearrangements including, developmental delay, craniofacial differences, cardiac defects and mild to severe mental retardation, many or all of these genes that are altered may have significant roles in early human development. We have several ongoing projects to further characterize these genomic disorders by analyzing the breakpoints of the rearrangements to elucidate the mechanism and functional characterization of the genes that are altered. We are also investigating the role of copy number or structural variation in common, complex diseases like Bipolar disorder and Schizophrenia. Analysis with high density arrays has also created a need for data analysis and management in my laboratory. Thus, development and refinement of computational tools for analysis and mining of high density datasets is another area of interest.
Rotation Projects for 2006-2007
Please contact Dr. Shaikh for details about available projects.
Elizabeth Geiger- Sr. Research Technician.
Chad Haldeman-Englert, MD - Post-doctoral Clinical Fellow
Jinhui Wang, PhD- Post-doctoral Research Fellow
Hung-Chun (James) Yu, PhD - Post-doctoral Research Fellow
- Assistant Professor of Genetics at University of Pennsylvania School of Medicine (2003 – 2009)
- Assistant Professor of Pediatrics at the Children's Hospital of Philadelphia (2007 – 2009)
- Assistant Professor of Pediatrics at University of Pennsylvania School of Medicine (2002 – 2007)
- Ph.D., Biochemstry & Molecular Biology, Louisiana State University Medical Center (1995)
- B.Sc., Life Sciences & Biochemistry, St. Xavier's College, Bombay University, India (1988)
- Gotter, A.L., Shaikh, T.H., Budarf, M.L., Rhodes, C.H., Emanuel, B.S.. A Palindrome- Mediated Mechanism Distinguishes Translocations Involving LCR-B of Chromosome 22q11.2. Hum Mol Genet.. Vol 13. 2004:103-115.
- Kurahashi H, Shaikh T, Takata M, Toda T, Emanuel BS. The constitutional t(1`7;22): Another translocation mediated by palindromic AT-rich repeats. Am J Hum Genet. Vol 72(3). 2003:733-738.
- Nimmakayalu, M.A, Gotter A.L., Shaikh T.H., Emanuel B.S.. A Novel Sequence-Based Approach to Localize Translocation Breakpoints Identifies the Molecular Basis of a t(4;22). Hum Mol. Genet.. Vol 12. 2003:2817-2825.
- Shaikh TH, Kurahashi H, Emanuel BS. Evolutionarily conserved duplications in 22q11 mediate deletions, duplications, translocations and genomic instability. Genet Med. Vol 3(1). 2001:6-13.
- Emanuel BS, Shaikh TH. Segmental duplications: An 'expanding' role in genomic instability and disease. Nature Reviews Genetics. Vol 2. 2001:791-800.
- Shaikh TH, Grochowski B, Emanuel B. Evolutionary Analyses of Low Copy Repeats (LCRs) on Human Chromosome 22.. Genome Sequencing and Biology Meeting at The Cold Spring Harbor Laboratory. 2001.
- Shaikh TH, Kurahaski H, Saitta SC, Hu P, Roe BA, Driscoll BS. Chromosome 22-specific low copy repeats (LCRs) and the 22q11.2 deletion syndrome: Genomic organization and deletion endpoint analysis. Hum Molec Genet. Vol 9(4). 2000:489-501.
- Shaikh TH, Kurahaski H, Hu P, Roe BA, Emanuel BS, Budarf ML. Regions of genomic instability on 22q11 and 11q23 as the etiology for the recurrent constitutional t(11;22). Hum Mol Genet. Vol 9(11). 2000:1665-1670.
- Kurahaski H, Shaikh TH, Zackai EH, Celle L, Driscoll DA, Budarf ML, Emanuel BS. Tightly clustered 11q23 and 22q11 breakpoints permit PCR based detection of the recurrent constitional t(11;22). Am J Hum Genet. Vol 67(3). 2000:763-768.
- Kurahashi H, Shaikh TH, Emanuel BS. Alu-mediated PCR artifacts and the constitutional t(11;22) breakpoint. Hum Mol Genet. Vol 9(18). 2000:2727-2732.