%X 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 neurodegeneration-associated 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.
%V 6
%A D Zhang
%A S Guelfi
%A S Garcia-Ruiz
%A B Costa
%A RH Reynolds
%A K D’Sa
%A W Liu
%A T Courtin
%A A Peterson
%A AE Jaffe
%A J Hardy
%A JA Botía
%A L Collado-Torres
%A M Ryten
%J Science Advances
%N 24
%L discovery10102309
%D 2020
%O This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
%T Incomplete annotation has a disproportionate impact on our understanding of Mendelian and complex neurogenetic disorders