Abstract
Genes are typically assumed to express both parental alleles similarly, yet cell lines show random allelic expression (RAE) for many autosomal genes that could shape genetic effects. Thus, understanding RAE in human tissues could improve our understanding of phenotypic variation. Here, we develop a methodology to perform genome-wide profiling of RAE and biallelic expression in GTEx datasets for 832 people and 54 tissues. We report 2,762 autosomal genes with some RAE properties similar to randomly inactivated X-linked genes. We found that RAE is associated with rapidly evolving regions in the human genome, adaptive signaling processes, and genes linked to age-related diseases such as neurodegeneration and cancer. We define putative mechanistic subtypes of RAE distinguished by gene overlaps on sense and antisense DNA strands, aggregation in clusters near telomeres, and increased regulatory complexity and inputs compared with biallelic genes. We provide foundations to study RAE in human phenotypes, evolution, and disease.