{Reference Type}: Journal Article
{Title}: Misexpression of inactive genes in whole blood is associated with nearby rare structural variants.
{Author}: Vanderstichele T;Burnham KL;de Klein N;Tardaguila M;Howell B;Walter K;Kundu K;Koeppel J;Lee W;Tokolyi A;Persyn E;Nath AP;Marten J;Petrovski S;Roberts DJ;Di Angelantonio E;Danesh J;Berton A;Platt A;Butterworth AS;Soranzo N;Parts L;Inouye M;Paul DS;Davenport EE;
{Journal}: Am J Hum Genet
{Volume}: 111
{Issue}: 8
{Year}: 2024 Aug 8
{Factor}: 11.043
{DOI}: 10.1016/j.ajhg.2024.06.017
{Abstract}: Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. Despite its known pathological consequences in specific rare diseases, we have a limited understanding of its wider prevalence and mechanisms in humans. To address this, we analyzed gene misexpression in 4,568 whole-blood bulk RNA sequencing samples from INTERVAL study blood donors. We found that while individual misexpression events occur rarely, in aggregate they were found in almost all samples and a third of inactive protein-coding genes. Using 2,821 paired whole-genome and RNA sequencing samples, we identified that misexpression events are enriched in cis for rare structural variants. We established putative mechanisms through which a subset of SVs lead to gene misexpression, including transcriptional readthrough, transcript fusions, and gene inversion. Overall, we develop misexpression as a type of transcriptomic outlier analysis and extend our understanding of the variety of mechanisms by which genetic variants can influence gene expression.