Fragile X gene instability: Anchoring AGGs and linked microsatellites
- Institute for Basic Research in Developmental Disabilities, Staten Island, NY (United States); and others
Interspersed AGGs within the FMR1 gene CGG repeat region may anchor the sequence and prevent slippage during replication. In order to detect the AGG position variations, we developed a method employing partial MnlI restriction analysis and analyzed X chromosomes from 187 males, including 133 normal controls (17 with 20-34 and 16 with 35-52 repeats), plus 54 fragile X premutations with 56-180 repeats. Among controls, the interspersed AGG positions were highly polymorphic, with heterozygosity of 91%. Among the control samples, 1.5% had no AGG positions, 25% had one, 71% had two, and 3% had three. Among the fragile X premutation samples, 63% had no AGG, while 37% had only one AGG. Analysis of premutation samples within fragile X families showed that variation occurred only within the 3{prime} end of the region. Thus, the instability was polar. Controls with {ge}15 pure CGG repeats were associated with the longest alleles of two nearby microsatellites, FRAXAC1 with 20-21 repeats and DXS548 with 202-206 bp and with increased microsatellite heterzygosity. The association of long pure CGG regions, as with fragile X chromosomes, with the longer and more heterozygous microsatellite alleles suggests they may be related mechanistically. Further, our results do not support a recent suggestion that the frequency of fragile X alleles may be increasing. Finally, analysis of a set of nonhuman primate samples showed that long pure CGG tracks are variable in size and are located within the 3{prime} region, which suggests that polar instability within FMR1 is evolutionarily quite old. 55 refs., 3 figs., 4 tabs.
- OSTI ID:
- 105243
- Journal Information:
- American Journal of Human Genetics, Vol. 57, Issue 2; Other Information: PBD: Aug 1995
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BASIC STUDIES
HUMAN X CHROMOSOME
CHROMOSOMAL ABERRATIONS
PATIENTS
HEREDITARY DISEASES
MENTAL DISORDERS
GENES
GENE MUTATIONS
INSTABILITY
STRUCTURE-ACTIVITY RELATIONSHIPS
MUTATION FREQUENCY
BIOLOGICAL MODELS
BIOLOGICAL EVOLUTION
SIZE
NUCLEOTIDES
POLYMERASE CHAIN REACTION
BIOLOGICAL MARKERS
AMINO ACID SEQUENCE