Possible Founder Effects for FRAXE Alleles Pornprot Limprasert, 1,2 Nan Zhong, 1 Julia R. Currie, 1 and W. Ted Brown 1 * 1 Department of Human Genetics, New York State Institute for Basic Research, Staten Island, New York 2 Department of Pathology, Faculty of Medicine, Prince of Songkla University, Songkla, Thailand To determine if FRAXE alleles may have haplotype associations with nearby micro- satellites, we analyzed 149 unrelated con- trol Caucasian X chromosomes for FRAXE GCC alleles along with five nearby micro- satellites. The microsatellites included three that are new; GT25, CA4, and CA5 lo- cated ∼24, ∼48, and ∼50 kb proximal to the FRAXE GCC repeat, and two that were iden- tified previously: DXS8091 and DXS1691, lo- cated ∼90 and ∼5 kb distal. No significant correlations between haplotypes for the proximal microsatellites were found. Sig- nificant correlations of FRAXE GCC repeats and distal microsatellite allele sizes, DXS8091 (r = 0.24) and DXS1691 (r = -0.40), were found. One haplotype, 18–19 of DXS8091-DXS1691, was present on 57% of chromosomes with ≥22 FRAXE repeats but present on only 10% with <22 repeats. We conclude that this distal haplotype associa- tion likely reflects a FRAXE allele founder effect. The lack of association or founder ef- fects seen for the three newly identified proximal markers, located within 50 kb of FRAXE GCC, may reflect an unusually high rate of mutation for these microsatellites or a higher rate of recombination in the proxi- mal region. Am. J. Med. Genet. 84:286–290, 1999. © 1999 Wiley-Liss, Inc. KEY WORDS: microsatellites; FRAXE; founder effect; triplet re- peats INTRODUCTION The most common form of X-linked mental retarda- tion is the fragile X syndrome which is associated with an unstable CGG repeat within the 5' end of the FMR1 gene [Oberle ´ et al., 1991; Verkerk et al., 1991; Yu et al., 1991]. Linkage disquilibrium between three nearby mi- crosatellites, DXS584, FRAXAC1, FRAXAC2, and frag- ile X chromosomes have been reported in several stud- ies [Richards et al., 1992, 1994; Oudet et al., 1993; Haataja et al., 1994; Syrrou et al., 1996; Chiurazzi et al., 1996]. The dinucleotide microsatellites, DXS548 (∼150 kb proximal), FRAXAC1 (∼7 kb proximal) and the complex three-part polymorphism FRAXAC2 (∼12 kb distal) tend to have allele sizes that correlate with FMR1 CGG allele sizes [Zhong et al., 1994, 1995; Brown et al., 1996a]. In addition, we have noted posi- tive size associations among the microsatellite alleles near to FMR1 [Brown et al., 1996a]. However, the poly- morphic GCC repeat sizes of FRAXE (∼600 kb distal to FMR1) have shown no correlation with the triplet re- peat sizes of normal control FMR1 chromosomes [Knight et al., 1993; Brown et al., 1996a; Murray et al., 1996] suggesting that the correlation of allele sizes may only be present within a limited distance. FRAXE GCC repeat expansion is related to the FRAXE syndrome of mild mental retardation. The ex- pansion mutations of FRAXE are relatively rare [Brown, 1996] and only a limited number of families with the FRAXE mutation have been described [Knight et al., 1994; Hamel et al., 1994; Mulley et al., 1995; Carbonell et al., 1996; Murgia et al., 1996]. Recently, a gene associated with the CpG island near to FRAXE was cloned and identified as FMR2 [Chakrabarti et al., 1996; Gecz et al., 1996; Gu et al., 1996]. So far, the relationship between nearby microsatellites and con- trol FRAXE GCC alleles have not been examined for possible founder effects. In order to determine whether allele sizes and haplotype associations might be pres- ent, similar to the FRAXA locus, we analyzed the allelic distributions of FRAXE GCC repeats and five nearby microsatellites in a control Caucasian population. We found haplotype associations between triplet repeats of FRAXE and two of the five microsatellites examined. MATERIALS AND METHODS We chose 149 Caucasian DNA samples with previ- ously known FRAXE GCC sizes as determined by poly- merase chain reaction (PCR) [Zhong et al., 1996]. These samples were selected randomly so as to have three approximately equal groups of FRAXE GCC re- peats: group 1  4–15 repeats (50 chromosomes), group 2  16–21 repeats (48 chromosomes) and group 3  22–36 repeats (51 chromosomes). We analyzed two dinucleotide microsatellite markers: DXS1691 located *Correspondence to: W. Ted Brown, Department of Human Ge- netics, New York State Institute for Basic Research, 1050 Forest Hill Road, Staten Island, NY 10314. Received 4 March 1998; Accepted 9 November 1998 American Journal of Medical Genetics 84:286–290 (1999) © 1999 Wiley-Liss, Inc.