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Mission

Our research is aimed at understanding the genetic basis of normal and abnormal brain development and behavior, particularly by elucidating the mechanisms and consequences of human chromosome abnormalities. In addition, we have strong interests in technology development for more sensitive detection of these clinically significant abnormalities.

Background

Gene dosage imbalances due to visible chromosome rearrangements have long been recognized as a major cause of mental retardation (MR) and birth defects. Emerging evidence is revealing that submicroscopic genomic imbalances, such as microdeletions or microduplications, not visible by routine G-banding analysis, also play a significant role in neurodevelopmental disorders, including MR, autism and epilepsy.

The mechanism for a subset of recurring chromosomal rearrangements, now referred to as “genomic disorders”, has been elucidated and shown to be due to the underlying DNA sequence structure. Highly homologous blocks of duplicated sequence, also known as segmental duplications, duplicons or low copy repeats (LCRs), have been identified that mediate rearrangements via non-allelic homologous recombination between misaligned copies of duplicated regions This mechanism can generate a variety of chromosomal aberrations including deletions, duplications and inversions. Approximately 5% of the human genome is comprised of segmentally duplicated sequences with a 10-fold enrichment in the pericentromeric and subtelomeric regions Interestingly, many of the genomic disorders identified to date, such as Williams syndrome (7q11.23), Prader-Willi/Angelman syndromes (15q11-q13), Smith-Magenis syndrome (17p11.2) and VCFS/DiGeorge syndrome (22q11.2), demonstrate a “centromere bias” in their localization consistent with the duplicon-rich nature of these regions.

Our laboratory previously developed a complete set of unique BAC clones for each human subtelomeric regions, which have been translated into a routine diagnostic test for children with unexplained mental retardation. Current efforts in collaboration with the Martin Lab include development of a “Molecular Ruler” for each telomeric region, which allows us to calibrate the exact size of any patient’s genomic imbalance. This will allow construction of a human gene dosage map at telomeres, and for high-resolution genotype-phenotype correlations for clinical prognosis. Array-based comparative genomic hybridization (aCGH) is being developed for rapid determination of breakpoints and deletion/duplication content of telomere imbalances.

Similar to our work in subtelomeric regions, we are now developing unique BAC clones and Molecular Rules adjacent to the pericentromeric repeats on each human chromosome arm. Such clones will be valuable in the identification and characterization of supernumerary marker chromosomes in patients, a significant clinical problem. Recent studies with these clones have provided surprising insights into the specific mechanism of small ring chromosome formation in humans, with important genetic counseling implications to families where such rings are identified.