FMR1 haplotype analyses among Indians: a weak founder effect and other findings

Abstract

This study on allelic/haplotypic fragile X associations evaluated using STR (DXS548, FRAXAC1, FRAXAC2) and SNP (ATL1) markers flanking the (CGG) n locus of FMR1 is the first report from the large ethnically complex Indian population. Results have been compared with allele/haplotype distributions reported for other major ethnic groups, including White Caucasians, Africans, and Pacific Asians. Though overall allele frequency distributions at the individual loci are more similar to Western Caucasians compared with others, significant differences are observed in haplotypic associations with the mutated X. The striking findings are: (1) high diversity and heterozygosity of haplotypes among fragile X chromosomes (n=40) and controls (n=262), including four haplotypes found exclusively in this study sample;(2) weak association of DXS548-FRAXAC1-FRAXAC2 haplotypes, 2-1-3, 6-3-3+ and 7-4-6+ with the disorder, and absence of White Caucasian fragile X haplotypes 6-4-4 and 6-4-5; (3) weak founder effect for the fragile X expansion mutation in the Indians; (4) lack of a continuum of haplotype-based FMR1 alleles between intermediate (CGG) n size ranges and expanded alleles; (5) exclusion of ATL1 as a candidate genetic indicator of FMR1 instability. The high STR-based haplotype diversity observed among fragile X lineages, irrespective of ethnic alliances, strongly suggests the inappropriateness of using STR haplotypes to infer predisposition to instability among ethnically separated fragile X pedigrees and may reiterate the need for identifying newer SNPs from this region to not only determine true founder effects for the fragile X mutation, but also decipher possible mechanisms leading to CGG instability.

Haplotype analysis at the FRAXA locus in an Indian population

“…In the FRAXAC2 locus, six alleles were identified by us namely, 151, 152, 153, 154, 155, and 156. Studies on the English [Macpherson et al, 1994], Finns [Zhong et al, 1994], African‐Americans [Crawford et al, 2000], population from Greece and Cyprus [Syrrou et al, 1996], and the northern population of India [Sharma et al, 2003] showed the most frequent allele to be 153 (4+), which is also the most frequent allele in our population represented in 42% of the normal population. The 154 (4) allele was found to be the most frequent allele in fragile X samples in this study and the North Indian study.…”

“…The heterozygosity of the control population (63.3%) studied by us is higher in comparison to the Chinese (33%), Thai (16.5%), and Caucasians (44%), which reflects the heterogeneity of the studied population. A study on an Indian population from the northern part of India [Sharma et al, 2003] also reveals a lower prevalence of the 194 allele, a situation similar to that observed among the populations of Cameroon and blacks in USA [Chiurazzi et al, 1996b and Crawford et al, 2000]. The modal allele 194 (46.6%) was found to be flanked by 192 at a frequency of 22.6% [Sharma et al, 2003].…”

“…A study on an Indian population from the northern part of India [Sharma et al, 2003] also reveals a lower prevalence of the 194 allele, a situation similar to that observed among the populations of Cameroon and blacks in USA [Chiurazzi et al, 1996b and Crawford et al, 2000]. The modal allele 194 (46.6%) was found to be flanked by 192 at a frequency of 22.6% [Sharma et al, 2003]. In the studied population from eastern India which is ethnically distinct from the North Indian population, the alleles 194 and 192 were present in almost equal frequencies of 43 and 41%, respectively.…”

“…This suggests the possibility that fragile X mutations are derived from a limited number of initial expansions representing a “founder effect.” Fragile X founder effects have been established in various populations of the world British [Macpherson et al, 1994], Finnish [Zhong et al, 1996], Japanese [Richards et al, 1994], Italian [Chiurazzi et al, 1996a], Argentineans [Bonaventure et al, 1998], Chileans [Jara et al, 1998], and Chinese [Zhong et al, 1999] where there appears to be a common genetic background on which FMR1 expressions have occurred. A study on the Indian population mainly from the northern part of the country [Sharma et al, 2003] revealed a high haplotype diversity and a weak founder effect possibly arising due to complex demographic heterogeneity of the population. There are some fragile X chromosomes, which carry other haplotypes suggesting that the mutations have arisen independently on other genetic backgrounds.…”

FMR1 CGG Repeat Patterns and Flanking Haplotypes in Three Asian Populations and Their Relationship With Repeat Instability

“…In addition to loss of AGG interruptions, studies of normal and fragile X chromosomes in various populations have indicated that a substantial proportion of fragile X chromosomes are in linkage disequilibrium (LD) with a small subset of flanking DXS548‐FRAXAC1‐FRAXAC2 microsatellite marker haplotypes (Bonaventure et al 1998; Eichler et al 1996; Larsen et al 2000; Patsalis et al 1999; Pekarik et al 1999; Poon et al 1999; Sharma et al 2003; Zhong et al 1994). Eichler et al (1996) identified two pathways leading to a full mutation at different mutational rates and occurring on different fragile X haplotypes.…”