A number of clinically significant human diseases are associated with translocations of chromosome 22 at q11, suggesting specificity of this site in chromosomal rearrangement. The disorders include: Supernumerary der(22), t(11;22) syndrome, DiGeorge syndrome, the Phl chromosome of chronic myelogenous leukemia (CML), t(8;22) of Burkitt's lymphoma, 5(11;22) of Ewing's sarcoma, and cat-eye syndrome. We plan to: 1) assign a linear sequence of breakpoints to the derivative 22 chromosome of these disorders by comparative mapping studies using high resolution cytogenetics and in situ hybridization of chromosome 22 specific DNA probes; 2) examine the constancy of the 22q11 breakpoint for the 11;22 translocation in different families, and of the 9;22 rearrangement for different individuals with Phl-positive CML, using restriction enzymes and Southern blot analysis of genomic DNA coupled with in situ hybridization of DNA probes; 3) study the organization of chromosome 22 with regard to a specific gene cluster by examining the role of the immunoglobulin lambda chain genes in these specific rearrangements; 4) clone and examine the DNA sequences adjacent to the breakpoints at 11q23 and 22q11 and compare the constitutional 11;22 translocation with the 11;22 of Ewing's sarcoma, as well as to other 22q11 rearrangements; and 5) select a single copy DNA sequence from the chromosome 22 library that maps proximal to C-lambda and in 22q11.1; identify the origin of the cat-eye chromosome by hybridization of this probe in situ; determine the copy number of this sequence in chromosomal and nonchromosomal DiGeorge syndrome patients by in situ hybridization or quantitative Southern blot analysis. The application of this combined molecular and high resolution cytogenetic approach to chromosome 22 is to gain insight into the relationship between chromosome structure, molecular organization and developmental disorder and will ultimately lead to a better understanding of the molecular basis of chromosomal rearrangement and disease. (6)
Showing the most recent 10 out of 92 publications
