Expansion of GAA trinucleotide repeats in mammals.

We have previously shown that GAA trinucleotide repeats have undergone significant expansion in the human genome. Here we present the analysis of the length distribution of all 10 nonredundant trinucleotide repeat motifs in 20 complete eukaryotic genomes (6 mammalian, 2 nonmammalian vertebrates, 4 arthropods, 4 fungi, and 1 each of nematode, amoebozoa, alveolate, and plant), which showed that the abundance of large expansions of GAA trinucleotide repeats is specific to mammals. Analysis of human-chimpanzee-gorilla orthologs revealed that loci with large expansions are species-specific and have occurred after divergence from the common ancestor. PCR analysis of human controls revealed large expansions at multiple human (GAA)(30+) loci; nine loci showed expanded alleles containing >65 triplets, analogous to disease-causing expansions in Friedreich ataxia, including two that are in introns of genes of unknown function. The abundance of long GAA trinucleotide repeat tracts in mammalian genomes represents a significant mutation potential and source of interindividual variability.

[1]  L. Pianese,et al.  Parental gender, age at birth and expansion length influence GAA repeat intergenerational instability in the X25 gene: pedigree studies and analysis of sperm from patients with Friedreich's ataxia. , 1998, Human molecular genetics.

[2]  R. Sinden,et al.  Length-dependent structure formation in Friedreich ataxia (GAA)n*(TTC)n repeats at neutral pH. , 2004, Nucleic acids research.

[3]  L. Singh,et al.  Genome-wide analysis of microsatellite repeats in humans: their abundance and density in specific genomic regions , 2003, Genome Biology.

[4]  L. Schöls,et al.  Differential stability of the (GAA)n tract in the Friedreich ataxia (STM7) gene , 1997, Human Genetics.

[5]  M. V. Katti,et al.  Differential distribution of simple sequence repeats in eukaryotic genome sequences. , 2001, Molecular biology and evolution.

[6]  H. Zoghbi,et al.  Fourteen and counting: unraveling trinucleotide repeat diseases. , 2000, Human molecular genetics.

[7]  M. Quail,et al.  The complex repeats of Dictyostelium discoideum. , 2001, Genome research.

[8]  J. Biedler,et al.  Non-LTR retrotransposons in the African malaria mosquito, Anopheles gambiae: unprecedented diversity and evidence of recent activity. , 2003, Molecular biology and evolution.

[9]  M. Pandolfo,et al.  Inhibitory Effects of Expanded GAA·TTC Triplet Repeats from Intron I of the Friedreich Ataxia Gene on Transcription and Replicationin Vivo * , 1998, The Journal of Biological Chemistry.

[10]  T. Ashizawa,et al.  The GAA triplet-repeat sequence in Friedreich ataxia shows a high level of somatic instability in vivo, with a significant predilection for large contractions. , 2002, Human molecular genetics.

[11]  M. Pandolfo,et al.  Sticky DNA, a Self-associated Complex Formed at Long GAA·TTC Repeats in Intron 1 of the Frataxin Gene, Inhibits Transcription* , 2001, The Journal of Biological Chemistry.

[12]  J. Jurka,et al.  Microsatellites in different eukaryotic genomes: survey and analysis. , 2000, Genome research.

[13]  E. Bradbury,et al.  GAA instability in Friedreich's Ataxia shares a common, DNA-directed and intraallelic mechanism with other trinucleotide diseases. , 1998, Molecular cell.

[14]  Madhusudhan W. Pandit,et al.  Triplet repeats in human genome: distribution and their association with genes and other genomic regions , 2003, Bioinform..

[15]  K. Usdin,et al.  The GAA*TTC triplet repeat expanded in Friedreich's ataxia impedes transcription elongation by T7 RNA polymerase in a length and supercoil dependent manner. , 2000, Nucleic acids research.

[16]  P. Patel,et al.  The GAA triplet-repeat expansion in Friedreich ataxia interferes with transcription and may be associated with an unusual DNA structure. , 1998, American journal of human genetics.

[17]  R. Wells,et al.  The intrinsically unstable life of DNA triplet repeats associated with human hereditary disorders. , 2001, Progress in nucleic acid research and molecular biology.

[18]  M. Stoneking,et al.  Phylogenetic Analysis of the Friedreich Ataxia GAA Trinucleotide Repeat , 2001, Journal of Molecular Evolution.

[19]  A Dürr,et al.  Clinical and genetic abnormalities in patients with Friedreich's ataxia. , 1996, The New England journal of medicine.

[20]  R. Williamson,et al.  Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene. , 1998, Journal of medical genetics.

[21]  D. Labuda,et al.  Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion , 2000, Neurology.

[22]  G. Dalgliesh,et al.  Expansion of GAA triplet repeats in the human genome: unique origin of the FRDA mutation at the center of an Alu. , 2004, Genomics.

[23]  S. Bidichandani,et al.  Genetic admixture of European FRDA genes is the cause of Friedreich ataxia in the Mexican population. , 2004, Genomics.

[24]  M. Pandolfo,et al.  The Friedreich ataxia GAA triplet repeat: premutation and normal alleles. , 1997, Human molecular genetics.

[25]  G. Reid,et al.  Phenotype correlation and intergenerational dynamics of the Friedreich ataxia GAA trinucleotide repeat. , 1997 .

[26]  B. Keats,et al.  Replication-mediated instability of the GAA triplet repeat mutation in Friedreich ataxia. , 2004, Nucleic acids research.

[27]  R. Wells,et al.  The chemistry and biology of unusual DNA structures adopted by oligopurine · oligopyrimidine sequences , 1988, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[28]  R. Gibbs,et al.  Somatic sequence variation at the Friedreich ataxia locus includes complete contraction of the expanded GAA triplet repeat, significant length variation in serially passaged lymphoblasts and enhanced mutagenesis in the flanking sequence. , 1999, Human molecular genetics.

[29]  V. Sgaramella,et al.  Frequency and coverage of trinucleotide repeats in eukaryotes. , 2003, Gene.

[30]  M. Koenig,et al.  Evolution of the Friedreich's ataxia trinucleotide repeat expansion: founder effect and premutations. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J. Bertranpetit,et al.  Incipient GAA repeats in the primate Friedreich ataxia homologous genes. , 1999, Molecular biology and evolution.

[32]  T. Ashizawa,et al.  Friedreich ataxia in carriers of unstable borderline GAA triplet‐repeat alleles , 2004, Annals of neurology.

[33]  M. Pandolfo,et al.  Sticky DNA: self-association properties of long GAA.TTC repeats in R.R.Y triplex structures from Friedreich's ataxia. , 1999, Molecular cell.

[34]  R. Festenstein,et al.  DNA triplet repeats mediate heterochromatin-protein-1-sensitive variegated gene silencing , 2003, Nature.

[35]  P. Patel,et al.  Friedreich's Ataxia: Autosomal Recessive Disease Caused by an Intronic GAA Triplet Repeat Expansion , 1996, Science.