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TARGETED, HIGH-RESOLUTION RNA SEQUENCING OF NON-CODING GENOMIC REGIONS ASSOCIATED WITH NEUROPSYCHIATRIC FUNCTIONS

View ORCID ProfileSimon A. Hardwick, Samuel D. Bassett, Dominik Kaczorowski, James Blackburn, Kirston Barton, Nenad Bartonicek, Shaun L. Carswell, Hagen U. Tilgner, Clement Loy, Glenda Halliday, Tim R. Mercer, View ORCID ProfileMartin A. Smith, John S. Mattick
doi: https://doi.org/10.1101/539882
Simon A. Hardwick
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
2Faculty of Medicine, UNSW Sydney, Kensington NSW 2052, Australia.
3Brain and Mind Research Institute & Center for Neurogenetics, Weill Cornell Medicine, New York NY 10065, USA.
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  • ORCID record for Simon A. Hardwick
Samuel D. Bassett
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
2Faculty of Medicine, UNSW Sydney, Kensington NSW 2052, Australia.
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Dominik Kaczorowski
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
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James Blackburn
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
2Faculty of Medicine, UNSW Sydney, Kensington NSW 2052, Australia.
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Kirston Barton
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
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Nenad Bartonicek
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
2Faculty of Medicine, UNSW Sydney, Kensington NSW 2052, Australia.
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Shaun L. Carswell
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
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Hagen U. Tilgner
3Brain and Mind Research Institute & Center for Neurogenetics, Weill Cornell Medicine, New York NY 10065, USA.
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Clement Loy
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
4Brain and Mind Centre & Faculty of Medicine and Health, The University of Sydney, Camperdown NSW 2006, Australia.
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Glenda Halliday
4Brain and Mind Centre & Faculty of Medicine and Health, The University of Sydney, Camperdown NSW 2006, Australia.
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Tim R. Mercer
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
2Faculty of Medicine, UNSW Sydney, Kensington NSW 2052, Australia.
5Altius Institute for Biomedical Sciences, Seattle WA 98121, USA.
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Martin A. Smith
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
2Faculty of Medicine, UNSW Sydney, Kensington NSW 2052, Australia.
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  • For correspondence: martinalexandersmith@gmail.com john.mattick@gtc.ox.ac.uk
John S. Mattick
1Genomics & Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst NSW 2010, Australia.
2Faculty of Medicine, UNSW Sydney, Kensington NSW 2052, Australia.
6Green Templeton College, Oxford OX2 6HG, UK.
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  • For correspondence: martinalexandersmith@gmail.com john.mattick@gtc.ox.ac.uk
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Abstract

The human brain is one of the last frontiers of biomedical research. Genome-wide association studies (GWAS) have succeeded in identifying thousands of haplotype blocks associated with a range of neuropsychiatric traits, including disorders such as schizophrenia, Alzheimer’s and Parkinson’s disease. However, the majority of single nucleotide polymorphisms (SNPs) that mark these haplotype blocks fall within non-coding regions of the genome, hindering their functional validation. While some of these GWAS loci may contain cis-acting regulatory DNA elements such as enhancers, we hypothesized that many are also transcribed into non-coding RNAs that are missing from publicly available transcriptome annotations. Here, we use targeted RNA capture (‘RNA CaptureSeq’) in combination with nanopore long-read cDNA sequencing to transcriptionally profile 1,023 haplotype blocks across the genome containing non-coding GWAS SNPs associated with neuropsychiatric traits, using post-mortem human brain tissue from three neurologically healthy donors. We find that the majority (62%) of targeted haplotype blocks, including 13% of intergenic blocks, are transcribed into novel, multi-exonic RNAs, most of which are not yet recorded in GENCODE annotations. We validated our findings with short-read RNA-seq, providing orthogonal confirmation of novel splice junctions and enabling a quantitative assessment of the long-read assemblies. Many novel transcripts are supported by independent evidence of transcription including cap analysis of gene expression (CAGE) data and epigenetic marks, and some show signs of potential functional roles. We present these transcriptomes as a preliminary atlas of non-coding transcription in human brain that can be used to connect neurological phenotypes with gene expression.

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Posted February 04, 2019.
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TARGETED, HIGH-RESOLUTION RNA SEQUENCING OF NON-CODING GENOMIC REGIONS ASSOCIATED WITH NEUROPSYCHIATRIC FUNCTIONS
Simon A. Hardwick, Samuel D. Bassett, Dominik Kaczorowski, James Blackburn, Kirston Barton, Nenad Bartonicek, Shaun L. Carswell, Hagen U. Tilgner, Clement Loy, Glenda Halliday, Tim R. Mercer, Martin A. Smith, John S. Mattick
bioRxiv 539882; doi: https://doi.org/10.1101/539882
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TARGETED, HIGH-RESOLUTION RNA SEQUENCING OF NON-CODING GENOMIC REGIONS ASSOCIATED WITH NEUROPSYCHIATRIC FUNCTIONS
Simon A. Hardwick, Samuel D. Bassett, Dominik Kaczorowski, James Blackburn, Kirston Barton, Nenad Bartonicek, Shaun L. Carswell, Hagen U. Tilgner, Clement Loy, Glenda Halliday, Tim R. Mercer, Martin A. Smith, John S. Mattick
bioRxiv 539882; doi: https://doi.org/10.1101/539882

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