During the next granting period I plan to continue our research along three major lines. First, we will complete the mapping of the WAGR region of 11p13. Our initial efforts will be directed toward completing a long range restriction map of this region followed by the isolation of the genomic DNA of this region by molecular cloning techniques. From these cloned DNA sequences we will develop a transcriptional map of this region. We will then identify transcripts responsible for the specific functional phenotypes identified with deletions of this region, aniridia, Wilms tumor, urogenital malformations and mental retardation by correlating the location of deletion and translocation breakpoints with the occurrence of these conditions in patients. A second goal of this proposal will be to extend our studies of homology between human chromosome 11 and other mammalian species. One main focus will be to characterize the region of mouse chromosome 2 which is likely to be homologous to the WAGR region of human chromosome 11. We will undertake a detailed effort to study the genetics and functional basis of mutations at the Sey locus on mouse chromosome 2 which we believe is likely to be a homologue to the human aniridia (AN-2) locus on chromosome 11. We will attempt to develop mice which are functionally hemozygous for the mouse homologue to the Wilms tumor gene and determine whether such animals exhibit a high frequency of malignancies derived from embryonic kidney tissue. A further goal of our mouse genetics program will be to continue to characterize homology relationships between other portions of human chromosome II and segments of mouse chromosomes 7 (llp15), 19 (llq13) and 9 (llq23). The third major objective of this proposal will be to continue develop and utilize molecular genetic and somatic genetic techniques to map chromosome 11 in its entirety. Continued effort will be directed towards the extension of studies on the short arm of the chromosome. Increased effort and emphasis will be placed on the long arm of the chromosome during the next granting period. In particular, we will utilize techniques and reagents developed during the previous granting period to isolate somatic cell hybrids for the long arm of the chromosome analogous to those which have been so useful in mapping IIp. Additional cloned genomic DNA segments for IIq will be isolated using these hybrids, and RFLPs will be identified for a subset of these genomic DNA clones, A detailed map of IIq will then be constructed using the combined power of somatic cell genetics, genetic linkage techniques and long range restriction mapping methods. We will utilize map information derived from our studies to test hypotheses regarding the location of genes for specific genetic disorders or predispositions on chromosome 11.
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