title: SMRT Sequencing of Long Tandem Nucleotide Repeats in SCA10 Reveals Unique Insight of Repeat Expansion Structure.
abstract: A large, non-coding ATTCT repeat expansion causes the neurodegenerative disorder, spinocerebellar ataxia type 10 (SCA10). In a subset of SCA10 patients, interruption motifs are present at the 5' end of the expansion and strongly correlate with epileptic seizures. Thus, interruption motifs are a predictor of the epileptic phenotype and are hypothesized to act as a phenotypic modifier in SCA10. Yet, the exact internal sequence structure of SCA10 expansions remains unknown due to limitations in current technologies for sequencing across long extended tracts of tandem nucleotide repeats. We used the third generation sequencing technology, Single Molecule Real Time (SMRT) sequencing, to obtain full-length contiguous expansion sequences, ranging from 2.5 to 4.4 kb in length, from three SCA10 patients with different clinical presentations. We obtained sequence spanning the entire length of the expansion and identified the structure of known and novel interruption motifs within the SCA10 expansion. The exact interruption patterns in expanded SCA10 alleles will allow us to further investigate the potential contributions of these interrupting sequences to the pathogenic modification leading to the epilepsy phenotype in SCA10. Our results also demonstrate that SMRT sequencing is useful for deciphering long tandem repeats that pose as "gaps" in the human genome sequence.
authors: Department of Neurology and The McKnight Brain Institute, University of Florida, Gainesville, Florida, 32610, United States of America.
authors: Karen N
authors: KN
authors: McFarland
authors: Department of Neurology and The McKnight Brain Institute, University of Florida, Gainesville, Florida, 32610, United States of America.
authors: Jilin
authors: J
authors: Liu
authors: Department of Neurology and The McKnight Brain Institute, University of Florida, Gainesville, Florida, 32610, United States of America.
authors: Ivette
authors: I
authors: Landrian
authors: Lucigen Corporation, Middleton, Wisconsin, 53562, United States of America.
authors: Ronald
authors: R
authors: Godiska
authors: Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, Florida, 32610, United States of America.
authors: Savita
authors: S
authors: Shanker
authors: Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, Florida, 32610, United States of America.
authors: Fahong
authors: F
authors: Yu
authors: Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, Florida, 32610, United States of America.
authors: William G
authors: WG
authors: Farmerie
authors: Department of Neurology and The McKnight Brain Institute, University of Florida, Gainesville, Florida, 32610, United States of America.
authors: Tetsuo
authors: T
authors: Ashizawa
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000483:Alleles; D000067736:Ataxin-10 / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D042622:DNA Repeat Expansion / Q000235:genetics; D004827:Epilepsy / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007438:Introns; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D020754:Spinocerebellar Ataxias / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: C503889:ATXN10 protein, human; D000067736:Ataxin-10