Evidence of founder chromosomes in fragile X syndrome

Ri, Richards; Holman, K.; Friend, K.; Kremer, Eric J.; D, Hillen; Staples, Alan; Wt, Brown; Goonewardena, P.; Tarleton, Jack; Schwartz, Charles E.

doi:10.1038/ng0792-257

Cited by 155 publications

(73 citation statements)

References 16 publications

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“…2). This finding suggests that different rates of normal-to-premutation, as proposed under the founder-haplotype hypothesis (Richards et al, 1992;Chakravarti, 1992;Jacobs et al, 1993), could be sufficient to yield substantial variation in carrier frequencies. This founder-haplotype hypothesis is also consistent with earlier reports that Asian and non-Asian populations may differ in their distributions of FMR1 alleles with various numbers and positions of AGG repeats within the CGGrepeat region (see, for example Hirst et al, 1997).…”

Section: Resultsmentioning

confidence: 77%

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

Genereux

Laird

2013

Genes Genet. Syst.

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Asian and non-Asian populations have been reported to differ substantially in the distribution of fragile X alleles into the normal (< 55 CGG repeats), premutation (55-199 CGG repeats), and full-mutation (> 199 CGG repeats) size classes. Our statistical analyses of data from published general-population studies confirm that Asian populations have markedly lower frequencies of premutation alleles, reminiscent of earlier findings for expanded alleles at the Huntington's Disease locus. To examine historical and contemporary factors that may have shaped and now sustain allele-frequency differences at the fragile X locus, we develop a population-genetic/epigenetic model, and apply it to these published data. We find that founder-haplotype effects likely contribute to observed frequency differences via substantially lower mutation rates in Asian populations. By contrast, any premutation frequency differences present in founder populations would have disappeared in the several millennia since initial establishment of these groups. Differences in the reproductive fitness of female premutation carriers arising from fragile X primary ovarian insufficiency (FXPOI) and from differences in mean maternal age may also contribute to global variation in carrier frequencies.

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Section: Resultsmentioning

confidence: 77%

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

Genereux

Laird

2013

Genes Genet. Syst.

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“…On the one hand, although instability-predisposing haplotypes have been demonstrated in other trinucleotide repeat-related human disorders, with specific haplotypes in linkage disequilibrium with repeat copy numbers at the high end of the normal range and with the expanded alleles, 18,23,28,[33][34][35][36][37][38][39][40][41][42][43] this does not seem to be the case in MJD, at least not in all populations. On the other hand, if there was a instability-predisposing haplotype, its effect should also be detectable on intergenerational instability of the expansion-carrying chromosomes, therefore there should be a noticeable effect of the haplotype on instability in cis, which we do not detect.…”

Section: Discussionmentioning

confidence: 99%

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract

et al. 1999

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Intergenerational instability is one of the most important features of the disease-associated trinucleotide expansions, leading to variation in size of the repeat among and within families, which manifests as variable age at onset and severity, and is probably the basis for the occurrence of anticipation. Several factors are known to affect the degree of instability, namely the type of repeated sequence, its initial size, the presence or absence of interruptions in the repetitive tract and the gender of the transmitting parent. A recent study demonstrated the effect of an intragenic polymorphism (C 987 GG/G 987 GG) in the Machado-Joseph disease causative gene, immediately downstream of the CAG repeat, on the intergenerational instability of the expanded repeat. Surprisingly, there was an effect not only of the specific allele in cis to the disease chromosome, but also of the allele on the normal chromosome, suggesting the existence of an interaction between the normal and expanded alleles that affects the fidelity of replication of the (CAG) n tract. This effect could be a direct effect of the polymorphism studied or, alternatively, this polymorphism could be in disequilibrium with some other flanking sequence which affects the instability of the repetitive (CAG) n tract. In order to confirm the previous results in a different population and to distinguish between a direct and indirect effect of the CGG/GGG polymorphism, we typed 70 parent-progeny pairs for which the variation in the (CAG) n length in the MJD1 gene was known, for three intragenic polymorphisms: C European Journal of Human Genetics (1999) 7, 147-156 © 1999 Stockton Press All rights reserved 1018-4813/99 $12.00 t http://www.stockton-press.co.uk/ejhg suggestive of an instability-predisposing effect of the repeat-flanking sequences, which could have led to the origin of the MJD mutation in the human population. We confirmed the effect of the C 987 GG/G 987 GG polymorphism on intergenerational instability when present in trans. Our results suggest that this effect is restricted to a small region of the gene, immediately downstream of the CAG repeat, which includes this particular nucleotide substitution and the stop codon of the MJD1 cDNA, and is not a more widespread chromosomal effect. The lack of a significant association of any specific intragenic haplotype with larger CAG repeats in normal chromosomes, together with the absence of an effect of the intragenic haplotype in cis on the intergenerational instability of the expanded (CAG) n in MJD families does not indicate the existence of an instability-predisposing haplotype.

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“…3), only the hexa-His and hexa-Asn tracts are encoded by a triplet repeat reminiscent of the genetic expansion of poly-Gln repeats associated with several neurodegenerative disorders (Richards et al, 1992). The functional significance, if any, of these repeats is unclear but none of them are conserved in LjNIN or the other NLPs.…”

Section: Domains Of the Psnin Proteinmentioning

confidence: 99%

The Sym35 Gene Required for Root Nodule Development in Pea Is an Ortholog of Nin from Lotus japonicus

et al. 2003

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Comparative phenotypic analysis of pea (Pisum sativum) sym35 mutants and Lotus japonicus nin mutants suggested a similar function for thePsSym35 and LjNin genes in early stages of root nodule formation. Both the pea and L.japonicus mutants are non-nodulating but normal in their arbuscular mycorrhizal association. Both are characterized by excessive root hair curling in response to the bacterial microsymbiont, lack of infection thread initiation, and absence of cortical cell divisions. To investigate the molecular basis for the similarity, we cloned and sequenced the PsNin gene, taking advantage of sequence information from the previously cloned LjNin gene. An RFLP analysis on recombinant inbred lines mapped PsNinto the same chromosome arm as the PsSym35 locus and direct evidence demonstrating that PsNin is thePsSym35 gene was subsequently obtained by cosegregation analysis and sequencing of three independent Pssym35mutant alleles. L. japonicus and pea root nodules develop through different organogenic pathways, so it was of interest to compare the expression of the two orthologous genes during nodule formation. Overall, a similar developmental regulation of thePsNin and LjNin genes was shown by the transcriptional activation in root nodules of L. japonicus and pea. In the indeterminate pea nodules,PsNin is highly expressed in the meristematic cells of zone I and in the cells of infection zone II, corroborating expression of LjNin in determinate nodule primordia. At the protein level, seven domains, including the putative DNA binding/dimerization RWP-RK motif and the PB1 heterodimerization domain, are conserved between the LjNIN and PsNIN proteins.

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Evidence of founder chromosomes in fragile X syndrome

Cited by 155 publications

References 16 publications

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

Study of three intragenic polymorphisms in the Machado-Joseph disease gene (MJD1) in relation to genetic instability of the (CAG)n tract

The Sym35 Gene Required for Root Nodule Development in Pea Is an Ortholog of Nin from Lotus japonicus

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