Journal Article

Introns control stochastic allele expression bias

Sands, Bryan, Yun, Soo, Mendenhall, Alexander R.

2021

Overview

Monoallelic expression (MAE) or extreme allele bias can account for incomplete penetrance, missing heritability and non-Mendelian diseases. In cancer, MAE is associated with shorter patient survival times and higher tumor grade. Prior studies showed that stochastic MAE is caused by stochastic epigenetic silencing, in a gene and tissue-specific manner. Here, we used C. elegans to study stochastic MAE in vivo. We found allele bias/MAE to be widespread within C. elegans tissues, presenting as a continuum from fully biallelic to MAE. We discovered that the presence of introns within alleles robustly decreases MAE. We determined that introns control MAE at distinct loci, in distinct cell types, with distinct promoters, and within distinct coding sequences, using a 5’-intron position-dependent mechanism. Bioinformatic analysis showed human intronless genes are significantly enriched for MAE. Our experimental evidence demonstrates a role for introns in regulating MAE, possibly explaining why some mutations within introns result in disease. Stochastic autosomal allele expression bias has been widely documented, yet the mechanisms behind this consequential phenomenon remain poorly understood. Here the authors show that the presence of introns greatly restricts monoallelic expression in a C. elegans model.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 14/35 / 38/35 / 42/44 / 42/62 / 631/208/176/2016 / 631/553/2707 / 64/11 / Alleles / Animals / Bias / Caenorhabditis elegans - genetics / Epigenetics / Heritability / Humanities and Social Sciences / In vivo methods and tests / Introns / Introns - genetics / multidisciplinary / Mutation / Mutation - genetics / Science / Science (multidisciplinary) / Tumors