Abstract:
:The fragile X syndrome is characterized at the molecular level by expansion and methylation of a CGG trinucleotide repeat located within the FMR1 locus. The tissues of most full mutation carriers are mosaic for repeat size, but these mutational patterns tend to be well conserved when comparing multiple tissues within an individual. Moreover, full mutation alleles are stable in cultured fibroblasts. These observations have been used to suggest that fragile X CGG repeat instability normally is limited to a period during early embryogenesis. DNA methylation of the repeat region is also believed to occur during early development, and some experimental evidence indicates that this modification may stabilize the repeats. To study the behavior of full mutation alleles in mitotic cells, we generated human-mouse somatic cell hybrids that carry both methylated and unmethylated full mutation FMR1 alleles. We observed considerable repeat instability and analyzed repeat dynamics in the hybrids as a function of DNA methylation, repeat length and cellular differentiation. Our results indicate that although DNA methylation does correlate with stability in primary human fibroblasts, it does not do so in the cell hybrids. Instead, repeat stability in the hybrids is dependent on repeat length, except in an undifferentiated cellular background where large alleles are maintained with a high degree of stability. This stability is lost when the cells undergo differentiation. These results indicate that the determinants of CGG repeat stability are more complex than generally believed, and suggest an unexpected role for cellular differentiation in this process.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Burman RW,Popovich BW,Jacky PB,Turker MSdoi
10.1093/hmg/8.12.2293subject
Has Abstractpub_date
1999-11-01 00:00:00pages
2293-302issue
12eissn
0964-6906issn
1460-2083pii
ddc256journal_volume
8pub_type
杂志文章abstract::Genomic data offer a goldmine of information for understanding the contribution of genetic variation makes to health and disease. The potential of genomic medicine, to predict, diagnose, manage and treat genetic disease, is underpinned by accurate variant interpretation. This in itself hinges on the ability to access ...
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