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Evolution of a Human-Specific Tandem Repeat Associated with ALS.
Course, Meredith M; Gudsnuk, Kathryn; Smukowski, Samuel N; Winston, Kosuke; Desai, Nitin; Ross, Jay P; Sulovari, Arvis; Bourassa, Cynthia V; Spiegelman, Dan; Couthouis, Julien; Yu, Chang-En; Tsuang, Debby W; Jayadev, Suman; Kay, Mark A; Gitler, Aaron D; Dupre, Nicolas; Eichler, Evan E; Dion, Patrick A; Rouleau, Guy A; Valdmanis, Paul N.
Affiliation
  • Course MM; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Gudsnuk K; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Smukowski SN; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Winston K; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Desai N; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Ross JP; Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.
  • Sulovari A; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
  • Bourassa CV; Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
  • Spiegelman D; Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
  • Couthouis J; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
  • Yu CE; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
  • Tsuang DW; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA 98108, USA.
  • Jayadev S; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Neurology, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • Kay MA; Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
  • Gitler AD; Department of Genetics, Stanford University, Stanford, CA 94305, USA.
  • Dupre N; Neuroscience Axis, CHU de Québec-Université Laval & Department of Medicine, Université Laval, Quebec City, QC G1J 1Z4, Canada.
  • Eichler EE; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
  • Dion PA; Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
  • Rouleau GA; Montreal Neurological Institute and Hospital, McGill University, Montreal, QC H3A 2B4, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3A 2B4, Canada.
  • Valdmanis PN; Division of Medical Genetics, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Electronic address: paulnv@uw.edu.
Am J Hum Genet ; 107(3): 445-460, 2020 09 03.
Article in En | MEDLINE | ID: mdl-32750315
ABSTRACT
Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Evolution, Molecular / Tandem Repeat Sequences / Adaptor Proteins, Signal Transducing / Amyotrophic Lateral Sclerosis Type of study: Risk_factors_studies Limits: Aged / Female / Humans / Male Language: En Journal: Am J Hum Genet Year: 2020 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Evolution, Molecular / Tandem Repeat Sequences / Adaptor Proteins, Signal Transducing / Amyotrophic Lateral Sclerosis Type of study: Risk_factors_studies Limits: Aged / Female / Humans / Male Language: En Journal: Am J Hum Genet Year: 2020 Type: Article Affiliation country: United States