Genetic variation and intergenerational FMR1 CGG-repeat stability in 100 unrelated three-generation families from the normal population

In order to identify genetic factors governing expansion of the CGG repeat in the FMR1 gene and to determine what predisposes or causes a normal stabl e allele to change to an unstable premutation allele, it is essential to st udy and understand the basis of normal variation. The aim of this study was to investigate genetic variation and intergenerational stability of the FM R1 COG-repeat region in 100 unrelated three-generation families from the ge neral population (651 meioses). The number of CGG-repeats in the FMR1 gene was determined in all 750 individuals from the 100 families (a total of 1,1 32 X-chromosomes), and the allele frequencies and variability were analyzed . Thirty-six different alleles (12-60 repeats) were seen with 30 (45.8%) as the most common allele; overall female heterozygosity was 73%. Most (>96%) of the normal array lengths were less than 40 repeats. Fifteen families wi th at least one allele equal to or greater than 40 repeats (40-60) were ide ntified; in one of these families there was an increase of one triplet repe at during transmission from a mother to son. These findings, together with future molecular analyses, may provide data to test proposed models that at tempt to explain the mutational process and the population dynamics of the triplet repeat region of the FMR1 gene, including the transition from norma l to unstable alleles, or to test other putative cisacting sequences that m ay be involved with instability in the FMR1 gene. (C) 1999 Wiley-Liss, Inc.