Incomplete annotation of disease-associated genes is limiting 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 Botia, Leonardo Collado-Torres & Mina Ryten

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May 06, 2019

Received Date: 30th April 19

There is growing evidence to suggest that human gene annotation remains incomplete, with a disproportionate impact on the brain transcriptome. We used RNA-sequencing data from GTEx to detect novel transcription in an annotation-agnostic manner across 13 human brain regions and 28 human tissues. We found that genes highly expressed in brain are significantly more likely to be re-annotated, as are genes associated with Mendelian and complex neurodegenerative disorders. We improved the annotation of 63% of known OMIM-morbid genes and 65% of those with a neurological phenotype. We determined that novel transcribed regions, particularly those identified in brain, tend to be poorly conserved across mammals but are significantly depleted for genetic variation within humans. As exemplified by SNCA, we explored the implications of re-annotation for Mendelian and complex Parkinson’s disease. We validated in silico and experimentally a novel, brain-specific, potentially protein-coding exon of SNCA. We release our findings as tissue-specific transcriptomes in BED format and via vizER: Together these resources will facilitate basic genomics research with the greatest impact on neurogenetics.

Read in full at bioRxiv.

This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

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Nature Communications

Nature Research, Springer Nature