Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles

Fragile X syndrome results from the expansion of a CGG repeat that is normally interrupted by occasional AGG triplets. Linkage disequilibrium suggests that certain normal haplotypes may contribute unequally to the pool of fragile X chromosomes. Sequence analysis of normal alleles demonstrates haplotype-specific variation of the cryptic nature of the repeat. Variation occurs principally at the 3' end of the repeat, suggesting stability differences between the leading and lagging strands of DNA replication. Normal alleles with greater than 24 perfect 3' CGG repeats appear more frequently on haplotypes overrepresented among fragile X chromosomes. Such alleles are found in 2% of normal chromosomes and could comprise the ancestral allelic pool from which fragile X chromosomes are derived. These data also may imply that equilibrium between certain predisposed alleles and fragile X expansions has not yet been attained, indicating ongoing evolutionary change at this locus.

[1]  J. Mandel,et al.  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. , 1993, American journal of human genetics.

[2]  W. Vogel,et al.  Mitotic stability of fragile X mutations in differentiated cells indicates early post–conceptional trinucleotide repeat expansion , 1993, Nature Genetics.

[3]  R. Sinden,et al.  Preferential DNA secondary structure mutagenesis in the lagging strand of replication in E. coli , 1991, Nature.

[4]  N. Morton,et al.  Population genetics of the fragile-X syndrome: multiallelic model for the FMR1 locus. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  David E. Housman,et al.  Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member , 1992, Cell.

[6]  K. Davies,et al.  Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation , 1993, Cell.

[7]  Hans Lehrach,et al.  The Huntington's disease candidate region exhibits many different haplotypes , 1992, Nature Genetics.

[8]  J. Sutcliffe,et al.  Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome , 1991, Cell.

[9]  A. Chakravarti.  Fragile X founder effect? , 1992, Nature Genetics.

[10]  H. Zoghbi,et al.  Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I , 1993, Nature Genetics.

[11]  R I Richards,et al.  Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n , 1991, Science.

[12]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[13]  K. Fischbeck,et al.  Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy , 1991, Nature.

[14]  R. Nussbaum,et al.  The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein , 1993, Cell.

[15]  Robert I. Richards,et al.  Simple repeat DNA is not replicated simply , 1994, Nature Genetics.

[16]  C. Amemiya,et al.  Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. , 1992, Science.

[17]  J. Sutcliffe,et al.  Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox , 1991, Cell.

[18]  E. Eichler,et al.  Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG–repeat , 1993, Nature Genetics.

[19]  W. Brown,et al.  Rapid Fragile X Carrier Screening and Prenatal Diagnosis Using a Nonradioactive PCR Test , 1993 .

[20]  Cecie Starr,et al.  Biology: The unity and diversity of life , 1978 .

[21]  T. Glover,et al.  Induction of sister chromatid exchanges at common fragile sites. , 1987, American journal of human genetics.

[22]  O. Onodera,et al.  Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA) , 1994, Nature Genetics.

[23]  A J Jeffreys,et al.  Characterization of a highly unstable mouse minisatellite locus: evidence for somatic mutation during early development. , 1989, Genomics.

[24]  J. Jiricny,et al.  A specific mismatch repair event protects mammalian cells from loss of 5-methylcytosine , 1987, Cell.

[25]  Ben A. Oostra,et al.  Absence of expression of the FMR-1 gene in fragile X syndrome , 1991, Cell.

[26]  W. Brown,et al.  Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome. , 1993, American journal of human genetics.

[27]  S. Warren,et al.  The fragile X syndrome: no evidence for any recent mutations. , 1993, Journal of medical genetics.

[28]  S. Thibodeau,et al.  Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population. , 1993, American journal of human genetics.

[29]  T. Ashizawa,et al.  An unstable triplet repeat in a gene related to myotonic muscular dystrophy. , 1992, Science.

[30]  J. Mandel,et al.  Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome , 1991, Science.

[31]  Robert I. Richards,et al.  Dynamic mutations: A new class of mutations causing human disease , 1992, Cell.

[32]  J. Weber.  Informativeness of human (dC-dA)n.(dG-dT)n polymorphisms. , 1990, Genomics.

[33]  J. Sutcliffe,et al.  DNA methylation represses FMR-1 transcription in fragile X syndrome. , 1992, Human molecular genetics.

[34]  D. Brutlag,et al.  Expression of the Drosophila type II topoisomerase is developmentally regulated. , 1988, Biochemistry.

[35]  D. Nelson,et al.  High resolution methylation analysis of the FMR1 gene trinucleotide repeat region in fragile X syndrome. , 1993, Human molecular genetics.

[36]  D. Loesch,et al.  Fragile-X syndrome: unique genetics of the heritable unstable element. , 1992, American journal of human genetics.

[37]  M. Méchali,et al.  Chromosomal replication initiates and terminates at random sequences but at regular intervals in the ribosomal DNA of Xenopus early embryos. , 1993, The EMBO journal.

[38]  D. Nelson,et al.  Advances in molecular analysis of fragile X syndrome. , 1994, JAMA.

[39]  L. Vassilev,et al.  Identification of an origin of bidirectional DNA replication in mammalian chromosomes , 1990, Cell.

[40]  J. Mandel,et al.  Origin of the expansion mutation in myotonic dystrophy , 1993, Nature Genetics.

[41]  A J Jeffreys,et al.  Allelic diversity at minisatellite MS205 (D16S309): evidence for polarized variability. , 1993, Human molecular genetics.

[42]  S. Warren,et al.  FMR1 protein: conserved RNP family domains and selective RNA binding. , 1993, Science.

[43]  N. Archidiacono,et al.  Cytological mapping of the human glucose-6-phosphate dehydrogenase gene distal to the fragile-X site suggests a high rate of meiotic recombination across this site. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Fuchs,et al.  Greater susceptibility to mutations in lagging strand of DNA replication in Escherichia coli than in leading strand. , 1993, Science.