Uncovering complexity
To identify the genetic drivers of neurological, neuromuscular, and neurodegenerative disorders scientists must have access to the complete genomic landscape, including regions previously deemed impossible to sequence, and the tools to examine the full range of genomic variation.
The PacBio Systems using Single Molecule, Real-Time (SMRT) Sequencing provide exceptionally long reads, uniform coverage and high consensus accuracy. This technology enables scientists to gain a more comprehensive understanding of the genetic basis of neurological disease through:
 | Targeting Sequencing of candidate genes with pre-designed capture panels or long-range PCR to enrich and sequence multi-kilobase fragments |
 | Variant Detection to phase alleles and screen for variants including SNPs, complex structural variants like repeat expansions, and long homopolymers |
 | RNA Sequencing of full-length isoforms of disease-relevant genes to characterize the complete landscape of gene-specific transcripts |
 | Epigenetics for a more complete picture of the underlying biological disease mechanisms |
Spotlight: Alzheimer’s Study Reveals First Somatic Gene Recombination Found in Human Neurons
Using an impressive array of novel and cutting-edge technologies, the scientists found evidence of significant recombination in the APP gene, which encodes amyloid precursor protein in neurons and has been associated with Alzheimer’s. Explore this research further.
Lee, M.-H. et al. 2018. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563(7733):639-645.
Spotlight: Sequencing ALS-causing repeat expansion using No-Amp targeted sequencing method
Scientists used both whole genome long-read sequencing and amplification-free targeted sequencing using the CRISPR/Cas9 system to gain base-level resolution of the notoriously challenging C9orf72 repeat expansion causing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
Ebbert, M. T. W. et al. 2018. Long-read sequencing across the C9orf72 ‘GGGGCC’ repeat expansion: implications for clinical use and genetic discovery efforts in human disease. Molecular Neurodegeneration, 13(1):46.
Learn more about the No-Amp targeted sequencing method.
Selected Resources
- Mitsuhashi, Satomi et al. (2019) Long-read sequencing for rare human genetic diseases. Journal of human genetics
- Manek, Rachna et al. (2019) 5’UTR-mediated regulation of Ataxin-1 expression. Neurobiology of disease
- Ishiura, Hiroyuki et al. (2019) Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nature genetics
- Mizuguchi, Takeshi et al. (2019) Detecting a long insertion variant in SAMD12 by SMRT sequencing: implications of long-read whole-genome sequencing for repeat expansion diseases. Journal of human genetics
- Mizuguchi, Takeshi et al. (2019) A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing. Journal of human genetics
- Zablotskaya, Alena et al. (2018) Mapping the landscape of tandem repeat variability by targeted long read single molecule sequencing in familial X-linked intellectual disability. BMC medical genomics
- Lee, Ming-Hsiang et al. (2018) Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature
- Cumming, Sarah A et al. (2018) De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1. European journal of human genetics
- Hughes, Timothy et al. (2018) Elevated expression of a minor isoform of ANK3 is a risk factor for bipolar disorder. Translational psychiatry
- Kondratyev, Nikolay et al. (2018) Prediction of smoking by multiplex bisulfite PCR with long amplicons considering allele-specific effects on DNA methylation. Clinical epigenetics
- Song, Janet H T et al. (2018) Characterization of a human-specific tandem repeat associated with bipolar disorder and schizophrenia. American journal of human genetics
- Höijer, Ida et al. (2018) Detailed analysis of HTT repeat elements in human blood using targeted amplification-free long-read sequencing. Human mutation
- Ebbert, Mark T W et al. (2018) Long-read sequencing across the C9orf72 ‘GGGGCC’ repeat expansion: implications for clinical use and genetic discovery efforts in human disease. Molecular neurodegeneration
- Ardui, Simon et al. (2018) Detecting AGG interruptions in females with a FMR1 premutation by long-read Single-Molecule Sequencing: A 1 year clinical experience. Frontiers in genetics
- Aneichyk, Tatsiana et al. (2018) Dissecting the causal mechanism of X-linked Dystonia-Parkinsonism by integrating genome and transcriptome assembly. Cell
- Ardui, Simon et al. (2018) Single molecule real-time (SMRT) sequencing comes of age: applications and utilities for medical diagnostics. Nucleic acids research
- Jacob-Hirsch, Jasmine et al. (2018) Whole-genome sequencing reveals principles of brain retrotransposition in neurodevelopmental disorders. Cell research
- Tseng, Elizabeth et al. (2019) The landscape of SNCA transcripts across synucleinopathies: New insights from long reads sequencing analysis BioRxiv
- Tseng, Elizabeth et al. (2017) Altered expression of the FMR1 splicing variants landscape in premutation carriers. Biochimica et Biophysica Acta
- Schüle, Birgitt et al. (2017) Parkinson’s disease associated with pure ATXN10 repeat NPJ Parkinson's Disease
- Korlach, Jonas et al. (2017) De novo PacBio long-read and phased avian genome assemblies correct and add to reference genes generated with intermediate and short reads. GigaScience
- Seppälä, Hanna et al. (2017) Single-molecule sequencing revealing the presence of distinct JC polyomavirus populations in patients with progressive multifocal leukoencephalopathy. The Journal of infectious diseases
- Ardui, Simon et al. (2017) Detecting AGG interruptions in male and female FMR1 premutation carriers by single-molecule sequencing. Human mutation
- Brykczynska, Urszula et al. (2016) CGG repeat-induced FMR1 silencing depends on the expansion size in human iPSCs and neurons carrying unmethylated full mutations. Stem cell reports
- Hartley, Stephen W et al. (2016) Alternative isoform analysis of Ttc8 expression in the rat pineal gland using a multi-platform sequencing approach reveals neural regulation. PloS one
- Tombácz, Dóra et al. (2016) Full-length isoform sequencing reveals novel transcripts and substantial transcriptional overlaps in a herpesvirus. PloS one
- Ashley, Euan A et al. (2016) Towards precision medicine. Nature reviews. Genetics
- Chaisson, Mark J P et al. (2015) Genetic variation and the de novo assembly of human genomes. Nature reviews. Genetics
- McFarland, Karen N. et al. (2015) SMRT Sequencing of long tandem nucleotide repeats in SCA10 reveals unique insight of repeat expansion structure. PloS one
- Koskinen, Lotta L E et al. (2015) Identification of a common risk haplotype for canine idiopathic epilepsy in the ADAM23 gene. BMC genomics
- You, Xintian et al. (2015) Neural circular RNAs are derived from synaptic genes and regulated by development and plasticity. Nature neuroscience
- Chaisson, Mark J P et al. (2015) Resolving the complexity of the human genome using single-molecule sequencing. Nature
- Doolan, Kyle M et al. (2015) Conformation dependent epitopes recognized by prion protein antibodies probed using mutational scanning and deep sequencing. Journal of molecular biology
- Pretto, Dalyir I et al. (2015) Differential increases of specific FMR1 mRNA isoforms in premutation carriers. Journal of medical genetics
- Poster: Underwood, Jason et al. (2020) A complete solution for full-length transcript sequencing using the PacBio Sequel II System
- Poster: Tsai, Yu-Chih et al. (2020) Amplification-free protocol for targeted enrichment of repeat expansion genomic regions and SMRT Sequencing
- Poster: Tseng, E. et al. (2019) Full-Length RNA-seq of Alzheimer brain on the PacBio Sequel II System
- Poster: Ekholm, J. M. et al. (2019) Structural variant in the RNA Binding Motif Protein, X-Linked 2 (RBMX2) gene found to be linked to bipolar disorder
- Poster: Ekholm, J. et al. (2019) Sequencing the previously unsequenceable using amplification-free targeted enrichment powered by CRISPR/Cas9
- Poster: McLaughlin, Ian et al. (2018) No-amp targeted SMRT sequencing using a CRISPR-Cas9 enrichment method
- Poster: Ekholm, J. et al. (2018) Amplification-free, CRISPR-Cas9 targeted enrichment and SMRT Sequencing of repeat-expansion disease causative genomic regions
- Poster: Clark, Tyson A. et al. (2018) Amplification-free targeted enrichment and SMRT Sequencing of repeat-expansion genomic regions
- Poster: Chakraborty, Shreyasee et al. (2018) Mitochondrial DNA sequencing using PacBio SMRT technology
- Poster: Ekholm, J. et al. (2017) Screening for causative structural variants in neurological disorders using long-read sequencing
- Poster: Ekholm, Jenny et al. (2017) Screening and characterization of causative structural variants for bipolar disorder in a significantly linked chromosomal region onXq24-q27 in an extended pedigree from a genetic isolate
- Poster: Clark, T. A. et al. (2017) Targeted SMRT Sequencing of difficult regions of the genome using a Cas9, non-amplification based method
- Poster: Eng, K. et al. (2016) Target enrichment using a neurology panel for 12 barcoded genomic DNA samples on the PacBio SMRT Sequencing platform
- Poster: Tassone, F. et al. (2016) Alternative splicing in FMR1 premutations carriers
- Poster: Kujawa, S. et al. (2016) A method for the identification of variants in Alzheimer’s disease candidate genes and transcripts using hybridization capture combined with long-read sequencing
- Poster: Sethuraman, A. et al. (2016) Characterization of the Poly-T variants in the TOMM40 gene using PacBio long reads
- Poster: Ekholm, J. et al. (2016) Enrichment of unamplified DNA and long-read SMRT Sequencing to unlock repeat expansion disorders
- Poster: Jenny Gu, Kevin Eng, Anand Sethuraman, Steve Kujawa et al. (2016) Multiplex target enrichment using barcoded multi-kilobase fragments and probe-based capture technologies
- Poster: Ekholm, Jenny et al. (2016) Candidate gene screening using long-read sequencing
- Poster: Ekholm, Jenny et al. (2016) Enrichment of unamplified DNA and long-read SMRT Sequencing in unlocking the underlying biological disease mechanisms of repeat expansion disorders
- Poster: Baybayan, Primo et al. (2016) Application specific barcoding strategies for SMRT Sequencing
- Mars, Kristin and Laird Smith, Melissa and Vinnere Pettersson, Olga and Hardigan, Michael (2020) Webinar: Sequencing 101 – How long-read sequencing improves access to genetic information
- (2020) Video: Introduction to PacBio highly accurate long-read sequencing
- Song, Janet (2018) ASHG PacBio Workshop: Characterization of a large, human-specific tandem repeat array associated with bipolar disorder and schizophrenia
- Korlach, Jonas (2018) ASHG PacBio Workshop: PacBio product updates and roadmap – announcing the release of new chemistry and software
- Tseng, Elizabeth (2018) ASHG PacBio Workshop: The Iso-Seq method for discovering alternative splicing in human diseases
- McFarland, Karen (2017) ASHG PacBio Workshop: Expansion sequence variations underlie distinct disease phenotypes in SCA10
- Ameur, Adam (2017) AGBT Virtual Poster: Analysis method for amplification-free SMRT sequencing and assessment on repeat expansions in Huntington’s disease
- Clark, T. A. and Tsai, Y. and Greenberg, D. (2017) AGBT Virtual Poster: Targeted SMRT Sequencing of difficult regions of the genome using a Cas9, non-amplification based method
- Paulin, Lars (2017) AGBT Virtual Poster: Single-molecule sequencing reveals the presence of distinct JC polyomavirus populations in patients with progressive multifocal leukoencephalopathy
- Lutz, Michael (2016) ASHG PacBio Workshop: Identification and characterization of informative genetic structural variants for neurodegenerative diseases
- Ashley, Euan (2016) ASHG PacBio Workshop: Towards precision medicine
- Tassone, F. and Olaby, R. and Tang, H. and Hickey, L and Tseng, E. (2016) ASHG Virtual Poster: Alternative splicing in FMR1 premutations carriers
- Wenger, Aaron (2016) Video: Using the Integrative Genomics Viewer (IGV) to visualize PacBio long-read SMRT Sequencing data
- Ashizawa, Tetsuo (2016) Nature Webinar: Large interrupted pentanucleotide repeats of SCA10
- SMRT Sequencing Brochure: Delivering highly accurate long reads to drive discovery in life science (2019)
- Application Brief: No-Amp targeted sequencing – Best Practices (2019)
- Application Brief: Long-read RNA sequencing – Best Practices (2019)
- PacBio Certified Service Providers (2019)
- Infographic: Structural variants and disease (2017)
- Application Note: Multiplex target enrichment using barcoded multi-kilobase fragments and probe-based capture technologies (2016)
- Epigenetics Application Brochure: Characterize the epigenetic landscape of your genome (2016)