Over 98% of cases of the fragile X syndrome are due to a dynamic repeat-sequence mutation in the FMR1 gene. The normal, stable repeat sequence consists of CGG triplet repeats interrupted by single AGG trinucleotide sequences. The initial mutation that predisposes the repeat region to become unstable is due to any mechanism that results in an increased number of uninterrupted CGG repeats in the 3' region. Factors that affect those mechanisms and factors affecting the subsequent hyper-expansion, eventually leading to the silencing of the gene and consequent mental retardation, have yet to be identified. However, there are intriguing preliminary data that suggest such factors exist. We propose to combine genetic epidemiological and population genetic approaches to characterize possible mechanisms and factors that influence both the initial mutation and expansion processes. At a population level, we will examine the haplotype background of FMR1 alleles using both microsatellite and single-base change polymorphic markers in a large Caucasian, a large African-American and smaller African, Asian and Native American populations to determine the history of the mutation and determine if unique mutation pathways can be defined. To test hypotheses resulting from these studies, sperm from males with specific repeat sequence structures and haplotype backgrounds will be used as an """"""""experimental"""""""" system to examine possible mutation processes and their rates. In addition, premutation carrier parent-carrier offspring transmissions ascertained from fragile X families will be used to examine factors that affected the expansion process. Finally, biological processes suggested by these data will be theoretically modeled and validated by empirical data. The fate and impact of the fragile X mutation on the general population will be examined using such methods. The results obtained from this detailed analysis of the dynamics of the mutation process will be an important preliminary step to determine the molecular mechanism of this sever mental retardation syndrome.
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