Killam Seminar Series presents “Identifying dynamics of tandem repeat expansions in human evolution and neurodegenerative disease using long-read sequencing”
Paul Valdmanis will present, “Identifying dynamics of tandem repeat expansions in human evolution and neurodegenerative disease using long-read sequencing”.
Registration available here.
Speaker: Paul Valdmanis, PhD
Assistant Professor, Department of Medicine, Division of Medical Genetics, University of Washington
Abstract: Over 40 tandem repeats undergo expansion events that lead to neurological disease. This number is likely an underestimate as many repeats are difficult to amplify using existing short read sequencing approaches. Through the use of long-read sequencing, we identified a 69 bp intronic variable number tandem repeat (VNTR) in WD repeat domain 7 (WDR7). The VNTR is expanded in a family with Amyotrophic Lateral Sclerosis (ALS) and exhibits significantly higher repeat copy number in three independent cohorts of individuals with sporadic ALS compared with matched controls, suggesting that it plays a role in modifying susceptibility to ALS. Each 69 bp repeat motif forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells – a common hallmark of neurodegenerative disease pathology. We performed multiplexed barcoded PacBio long-read sequencing to resolve the complete internal structure of the WDR7 repeat in 288 geographically diverse individuals. We found striking variability in both repeat length and internal nucleotide composition. Some of the 69 bp repeat motifs are specifically present or absent in certain geographic populations, and we identified common repeat motifs in both Denisovan and Neanderthal genomes. We found that the repeat expands in the 3′-5′ direction, in groups of two repeat units. Extending this analysis to characterize VNTRs genome-wide, we identified several VNTRs that can differ in length (by up to 20 kb) amongst individuals and geographical super-populations and repeats that exhibit substantial diversity in internal sequence composition of the repeat. By characterizing the WDR7 VNTR in ALS, we identify features associated with repeat expansion dynamics, the mechanistic consequences of repeat expansions to ALS susceptibility, and the structure of repeats in geographically diverse populations that can precipitate expansion events.
Bio: Paul Valdmanis is an Assistant Professor in the Department of Medicine, Division of Medical Genetics and an Adjunct Assistant Professor in the Department of Genome Sciences at the University of Washington in Seattle, Washington. His research laboratory works to identify genetic and molecular contributions to neurodegenerative disease including Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s disease (AD) with a particular emphasis on long-read sequencing of tandem repeat expansions. His group then uses gene therapy methods for therapeutic intervention in ALS and AD. Dr. Valdmanis has worked extensively to determine the genetic basis of neurodegenerative disease during his doctoral studies at McGill University in the Department of Human Genetics. He has made seminal discoveries including the first identification of mutations in TDP-43 in patients with ALS, mutations in KIAA0196 (Strumpellin) in patients with Hereditary Spastic Paraplegia and an RNF170 mutation in a novel form of Autosomal Dominant Sensory Ataxia. Dr. Valdmanis completed his postdoctoral studies in the laboratory of Mark Kay at Stanford University. There he optimized methods to fine-tune gene regulation through use of microRNAs and determined the consequences of aberrant microRNA activation in lung and liver cancer. Furthermore, he has established gene therapy methods to safely and efficiently reduce target genes through use of adeno-associated viral delivery of small hairpin RNAs and identified a mechanism by which small hairpin RNAs compete with endogenous microRNAs. Dr. Valdmanis has published over 50 manuscripts, including 21 for which he is the first or co-first author. His work has been cited over 7000 times with an H-index of 28. He is the recipient of a Banting postdoctoral fellowship, a Bisby postdoctoral fellowship, a Governor General’s Gold Medal at McGill University and a Robert F. Schoeni Award for Research from Ann Arbor Active Against ALS.
Supported by the generosity of the Killam Trusts , The Neuro’s Killam Seminar series hosts outstanding guest speakers whose research is of interest to the scientific community at The Neuro and McGill University.