Linkage disequilibrium between the fragile X mutation and two closely linked CA repeats suggests that fragile X chromosomes are derived from a small number of founder chromosomes.
In order to investigate the origin of mutations responsible for the fragile X syndrome, two polymorphic CA repeats, one at 10 kb (FRAXAC2) and the other at 150 kb (DXS548) from the mutation target, were analyzed in normal and fragile X chromosomes. Contrary to observations made in myotonic dystrophy, fragile X mutations were not strongly associated with a single allele at the marker loci. However, significant differences in allelic and haplotypic distributions were observed between normal and fragile X chromosomes, indicating that a limited number of primary events may have been at the origin of most present-day fragile X chromosomes in Caucasian populations. We propose a putative scheme with six founder chromosomes from which most of the observed fragile X-linked haplotypes can be derived directly or by a single event at one of the marker loci, either a change of one repeat unit or a recombination between DXS548 and the mutation target. Such founder chromosomes may have carried a number of CGG repeats in an upper-normal range, from which recurrent multistep expansion mutations have arisen.
Oudet
C
C
Laboratoire de Génétique Moléculaire des Eucaryotes du CNRS, Unité 184 de l'INSERM, Strasbourg, France.
Mornet
E
E
Serre
J L
JL
Thomas
F
F
Lentes-Zengerling
S
S
Kretz
C
C
Deluchat
C
C
Tejada
I
I
Boué
J
J
Boué
A
A
D000483:Alleles; D004276:DNA, Satellite / Q000032:analysis; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics*; D005787:Gene Frequency; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D016296:Mutagenesis; D012150:Polymorphism, Restriction Fragment Length; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA
D004276:DNA, Satellite; D005819:Genetic Markers