Incomplete annotation has a disproportionate impact on our understanding of Mendelian and complex neurogenetic disorders

David Zhang, Sebastian Guelfi, Sonia Garcia-Ruiz, Beatrice Costa, Regina H. Reynolds, Karishma D’Sa, Wenfei Liu, Thomas Courtin, Amy Peterson, Andrew E. Jaffe, John Hardy, Juan A. Botía, Leonardo Collado-Torres, Mina Ryten

Research output: Contribution to journalArticle

Abstract

Growing evidence suggests that human gene annotation remains incomplete; however, it is unclear how this affects different tissues and our understanding of different disorders. Here, we detect previously unannotated transcription from Genotype-Tissue Expression RNA sequencing data across 41 human tissues. We connect this unannotated transcription to known genes, confirming that human gene annotation remains incomplete, even among well-studied genes including 63% of the Online Mendelian Inheritance in Man–morbid catalog and 317 neurodegenerationassociated genes. We find the greatest abundance of unannotated transcription in brain and genes highly expressed in brain are more likely to be reannotated. We explore examples of reannotated disease genes, such as SNCA, for which we experimentally validate a previously unidentified, brain-specific, potentially protein-coding exon. We release all tissue-specific transcriptomes through vizER: http://rytenlab.com/browser/app/vizER. We anticipate that this resource will facilitate more accurate genetic analysis, with the greatest impact on our understanding of Mendelian and complex neurogenetic disorders.

Original languageEnglish (US)
Article numbereaay8299
JournalScience Advances
Volume6
Issue number24
DOIs
StatePublished - Jun 2020

ASJC Scopus subject areas

  • General

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    Zhang, D., Guelfi, S., Garcia-Ruiz, S., Costa, B., Reynolds, R. H., D’Sa, K., Liu, W., Courtin, T., Peterson, A., Jaffe, A. E., Hardy, J., Botía, J. A., Collado-Torres, L., & Ryten, M. (2020). Incomplete annotation has a disproportionate impact on our understanding of Mendelian and complex neurogenetic disorders. Science Advances, 6(24), [eaay8299]. https://doi.org/10.1126/sciadv.aay8299