Widespread naturally variable human exons aid genetic interpretation.

Abstract

Most mammalian genes undergo alternative splicing. The splicing of some exons has been acquired or lost in specific mammalian lineages, but differences in splicing within the human population are poorly understood. Using GTEx tissue transcriptomes from 838 individuals, we identified 57,271 "naturally variable exons" (NVEs) - exons which are included in mRNAs in some individuals but entirely excluded from others (or vice versa). NVEs impact three quarters of protein-coding genes, occur at all population frequencies, and are often absent from reference annotations. NVEs are more abundant in genes depleted of genetic loss-of-function mutations and aid in the interpretation of causal genetic variants. Genetic variants modulate the splicing of many NVEs, and 5' untranslated region and coding-region NVEs are often associated with increased and decreased gene expression, respectively. Together, our findings characterize abundant splicing variation in the human population, with implications for a range of human genetic analyses.