Biomaterial Database

Fragile X founder chromosome effects: linkage disequilibrium or microsatellite heterogeneity? 1994

N Zhong, and L Ye, and C Dobkin, and W T Brown

Department of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, Staten Island 10314.

Previous studies of founder chromosome effects in fragile X have been based on linkage disequilibrium with either FRAXAC1 or DXS548 alone or combined with FRAXAC2. Recently, we found no linkage disequilibrium of FMR-1 with FRAXAC2, but rather, found FRAXAC2 was complex and highly mutable. Therefore, we have now analyzed FRAXAC1 and DXS548 together for haplotypes, two markers which have not been jointly analyzed previously, to test for disequilibrium. We typed 315 fragile X (FX) chromosomes and controls, further subdivided into large controls (LC) and small controls (SC) with < or = 35 repeats and identified 26 different haplotypes. Two were more frequent and one less frequent in FX than SCs, thus confirming apparent linkage disequilibrium in fragile X. However, we noted increased FX microsatellite heterozygosity, either individually (results quite similar to previous studies) or as haplotypes. This heterozygosity covaried with FX > LC > SC, which may indicate alternative explanation exists for the apparent disequilibrium. We hypothesize that large FMR-1 CGG repeat allele genes may be associated with the generation of new microsatellite mutations. Possible mechanisms include gene conversions between CGG repeats and flanking microsatellites involving unequal double cross-overs, the expansion of small control CGGs to larger sizes associated with episodic generalized microsatellite instability or as a direct result of mutant FMR-1 gene function. We conclude that the founder effects observed with the use of these CA repeats is likely to reflect both linkage disequilibrium and increased microsatellite instability of fragile X chromosomes.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D008969	Molecular Sequence Data	Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.	Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D009154	Mutation	Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.	Mutations
D009518	New York	State bounded on the north by Lake Ontario and Canada, on the east by Vermont, Massachusetts, and Connecticut, on the south by the Atlantic Ocean, New Jersey, and Pennsylvania, and on the west by Pennsylvania, Lake Erie, and Canada.
D012091	Repetitive Sequences, Nucleic Acid	Sequences of DNA or RNA that occur in multiple copies. There are several types: INTERSPERSED REPETITIVE SEQUENCES are copies of transposable elements (DNA TRANSPOSABLE ELEMENTS or RETROELEMENTS) dispersed throughout the genome. TERMINAL REPEAT SEQUENCES flank both ends of another sequence, for example, the long terminal repeats (LTRs) on RETROVIRUSES. Variations may be direct repeats, those occurring in the same direction, or inverted repeats, those opposite to each other in direction. TANDEM REPEAT SEQUENCES are copies which lie adjacent to each other, direct or inverted (INVERTED REPEAT SEQUENCES).	DNA Repetitious Region,Direct Repeat,Genes, Selfish,Nucleic Acid Repetitive Sequences,Repetitive Region,Selfish DNA,Selfish Genes,DNA, Selfish,Repetitious Region, DNA,Repetitive Sequence,DNA Repetitious Regions,DNAs, Selfish,Direct Repeats,Gene, Selfish,Repeat, Direct,Repeats, Direct,Repetitious Regions, DNA,Repetitive Regions,Repetitive Sequences,Selfish DNAs,Selfish Gene
D003434	Crossing Over, Genetic	The reciprocal exchange of segments at corresponding positions along pairs of homologous CHROMOSOMES by symmetrical breakage and crosswise rejoining forming cross-over sites (HOLLIDAY JUNCTIONS) that are resolved during CHROMOSOME SEGREGATION. Crossing-over typically occurs during MEIOSIS but it may also occur in the absence of meiosis, for example, with bacterial chromosomes, organelle chromosomes, or somatic cell nuclear chromosomes.	Crossing Over,Crossing-Over, Genetic,Crossing Overs,Genetic Crossing Over,Genetic Crossing-Over
D004276	DNA, Satellite	Highly repetitive DNA sequences found in HETEROCHROMATIN, mainly near centromeres. They are composed of simple sequences (very short) (see MINISATELLITE REPEATS) repeated in tandem many times to form large blocks of sequence. Additionally, following the accumulation of mutations, these blocks of repeats have been repeated in tandem themselves. The degree of repetition is on the order of 1000 to 10 million at each locus. Loci are few, usually one or two per chromosome. They were called satellites since in density gradients, they often sediment as distinct, satellite bands separate from the bulk of genomic DNA owing to a distinct BASE COMPOSITION.	Satellite DNA,Satellite I DNA,DNA, Satellite I,DNAs, Satellite,DNAs, Satellite I,I DNA, Satellite,I DNAs, Satellite,Satellite DNAs,Satellite I DNAs
D005260	Female		Females
D005600	Fragile X Syndrome	A condition characterized genotypically by mutation of the distal end of the long arm of the X chromosome (at gene loci FRAXA or FRAXE) and phenotypically by cognitive impairment, hyperactivity, SEIZURES, language delay, and enlargement of the ears, head, and testes. INTELLECTUAL DISABILITY occurs in nearly all males and roughly 50% of females with the full mutation of FRAXA. (From Menkes, Textbook of Child Neurology, 5th ed, p226)	FRAXA Syndrome,FRAXE Syndrome,Martin-Bell Syndrome,Fra(X) Syndrome,Fragile X Mental Retardation Syndrome,Fragile X-F Mental Retardation Syndrome,Mar (X) Syndrome,Marker X Syndrome,Mental Retardation, X-Linked, Associated With Fragile Site Fraxe,Mental Retardation, X-Linked, Associated With Marxq28,X-Linked Mental Retardation and Macroorchidism,FRAXA Syndromes,FRAXE Syndromes,Fragile X Syndromes,Marker X Syndromes,Martin Bell Syndrome,Syndrome, FRAXA,Syndrome, FRAXE,Syndrome, Fragile X,Syndrome, Marker X,Syndrome, Martin-Bell,Syndromes, FRAXA,Syndromes, FRAXE,Syndromes, Fragile X,Syndromes, Marker X,X Linked Mental Retardation and Macroorchidism
D005787	Gene Frequency	The proportion of one particular in the total of all ALLELES for one genetic locus in a breeding POPULATION.	Allele Frequency,Genetic Equilibrium,Equilibrium, Genetic,Allele Frequencies,Frequencies, Allele,Frequencies, Gene,Frequency, Allele,Frequency, Gene,Gene Frequencies