@article{cc4c5eea661d4cac9aeabaa8f458d4fd,
title = "Replication-Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease",
abstract = "Background: SNCA multiplication is a genomic cause of familial PD, showing dosage-dependent toxicity. Until now, nonallelic homologous recombination was suggested as the mechanism of SNCA duplication, based on various types of repetitive elements found in the spanning region of the breakpoints. However, the sequence at the breakpoint was analyzed only for 1 case. Objectives: We have analyzed the breakpoint sequences of 6 patients with PD who had duplicated SNCA using whole-genome sequencing data to elucidate the mechanism of SNCA duplication. Methods: Six patient samples with SNCA duplication underwent whole-genome sequencing. The duplicated regions were defined with nucleotide-resolution breakpoints, which were confirmed by junction polymerase chain reaction and Sanger sequencing. The search for potential non-B DNA-forming sequences and stem-loop structure predictions was conducted. Results: Duplicated regions ranged from the smallest region of 718.3 kb to the largest one of 4,162 kb. Repetitive elements were found at 8 of the 12 breakpoint sequences on each side of the junction, but none of the pairs shared overt homologies. Five of these six junctions had microhomologies (2–4 bp) at the breakpoint, and a short stretch of sequences was inserted in 3 cases. All except one junction were located within or next to stem-loop structures. Conclusion: Our study has determined that homologous recombination mechanisms involving repetitive elements are not the main cause of the duplication of SNCA. The presence of microhomology at the junctions and their position within stem-loop structures suggest that replication-based rearrangements may be a common mechanism for SNCA amplification.",
keywords = "FoSTeS, MMBIR, Parkinson's disease, SNCA duplication, microhomology",
author = "Seo, {Soo Hyun} and Albino Bacolla and Dallah Yoo and Koo, {Yoon Jung} and Cho, {Sung Im} and Kim, {Man Jin} and Seong, {Moon Woo} and Kim, {Han Joon} and Kim, {Jong Min} and Tainer, {John A.} and Park, {Sung Sup} and Kim, {Ji Yeon} and Beomseok Jeon",
note = "Funding Information: Dr. Beomseok Jeon has received research support Seoul National University College of Medicine, Seoul National University Hospital, Sinyang Cultural Foundation, Peptron, and AbbVie Korea. Dr. Sung Sup Park has received research support from Korea Rare‐disease Genetic Diagnostics Project (KRGDP), Korea Centers for Disease Control and Prevention. Dr. Moon‐Woo Seong has received research support from Korea Health Technology R&D Project, Korea Health Industry Development Institute (KHIDI), Ministry of Health & Welfare, and Republic of Korea. Dr.Han‐Joon Kim has received travel grants from International Parkinson and Movement Disorder Society, Korean Movement Disorder Society; research grants from C‐TRI, Institute of Information and Communication Technology Promotion, Seoul National University Hospital, and New York University. Funding Information: This research was supported, in part, by the National Cancer Institute grant CA092584 to J.A.T. This work used the Extreme Science and Engineering Discovery Environment (XSEDE) Bridges at the Pittsburgh Supercomputing Center through allocation MCB170053. We thank Dr. Davide Moiani for help with PyMOL. Funding Information: This research was supported, in part, by the National Cancer Institute grant CA092584 to J.A.T. This work used the Extreme Science and Engineering Discovery Environment (XSEDE) Bridges at the Pittsburgh Supercomputing Center through allocation MCB170053. We thank Dr. Davide Moiani for help with PyMOL. Publisher Copyright: {\textcopyright} 2020 International Parkinson and Movement Disorder Society",
year = "2020",
month = may,
day = "1",
doi = "10.1002/mds.27998",
language = "English (US)",
volume = "35",
pages = "868--876",
journal = "Movement Disorders",
issn = "0885-3185",
publisher = "John Wiley and Sons Inc.",
number = "5",
}