N. Zhong et al., FRAGILE-X FOUNDER CHROMOSOME EFFECTS - LINKAGE DISEQUILIBRIUM OR MICROSATELLITE HETEROGENEITY, American journal of medical genetics, 51(4), 1994, pp. 405-411
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 o
f 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 previ
ously, to test for disequilibrium. We typed 315 fragile X (FX) chromos
omes and controls, further subdivided into large controls (LC) and sma
ll controls (SC) with less than or equal to 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 fra
gile 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 disequilibriu
m. We hypothesize that large FMR-1 CGG repeat allele genes may be asso
ciated with the generation of new microsatellite mutations. Possible m
echanisms include gene conversions between CGG repeats and flanking mi
crosatellites involving unequal double cross-overs, the expansion of s
mall 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 a
nd increased microsatellite instability of fragile X chromosomes. (C)
1994 Wiley-Liss, Inc.