title: Modeling methylation and IQ scores in fragile X females and mosaic males.
abstract: Both fragile X females and mosaic males carry a methylated FMR1 allele in some cells and an unmethylated allele in other cells. Due to FMR1 protein produced in cells with an unmethylated allele, these individuals are expected to display a less severe cognitive phenotype than non-mosaic affected males. A larger range in cognitive abilities is expected for these individuals due to individual variation in X-inactivation or mosaicism ratios. These cognitive effects are well documented for females and have been suggested for mosaic males. Data on fragile X females suggest an approximately linear decrease in mean IQ score as a function of the fraction of cells with the mutation carried on the active X chromosome. Analysis of these data suggests that threshold effects in the relationship between IQ score and X-inactivation ratios are negligible, and that X-inactivation occurs randomly (with no preferential inactivation of either X chromosome) at a stage when the embryo consists of approximately 5 cells. A similar analysis of future data on mosaic males could yield estimates of the probability that a given cell will carry a methylated FMR1 allele and of the number of embryonic cells at the time that mosaicism is established. Distributions of IQ scores among a population of heterozygotes or mosaic male are predicted for several values of these parameters. These distributions include random contributions to IQ scores due to non-fragile-X-related effects, as well as X-inactivation or mosaicism ratios that vary from one individual to another.
authors.affiliation: Department of Physics, California State University, San Bernardino 92407-2397.
authors.forename: K
authors.initials: K
authors.lastname: Kolehmainen
authors.forename: Y
authors.initials: Y
authors.lastname: Karant
mesh_terms: D000483:Alleles; D016010:Binomial Distribution; D004247:DNA / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000378:metabolism; D004303:Dosage Compensation, Genetic; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D007360:Intelligence / Q000235:genetics*; D007361:Intelligence Tests; D008297:Male; D008745:Methylation; D008957:Models, Genetic; D009010:Monte Carlo Method; D009030:Mosaicism
chemical_list: D004247:DNA; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide