RT Journal Article
SR Electronic
T1 Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 038687
DO 10.1101/038687
A1 Sujatha Jagannathan
A1 Robert K. Bradley
YR 2016
UL http://biorxiv.org/content/early/2016/09/16/038687.abstract
AB Genetic variants that disrupt protein-coding DNA are ubiquitous in the human population, with ~100 such loss-of-function variants per individual. While most loss-of-function variants are rare, a subset have risen to high frequency and occur in a homozygous state in healthy individuals. It is unknown why these common variants are well-tolerated, even though some affect essential genes implicated in Mendelian disease. Here, we combine genomic, proteomic, and biochemical data to demonstrate that many common nonsense variants do not ablate protein production from their host genes. We provide computational and experimental evidence for diverse mechanisms of gene rescue, including alternative splicing, stop codon readthrough, alternative translation initiation, and C-terminal truncation. Our results suggest a molecular explanation for the mild fitness costs of many common nonsense variants, and indicate that translational plasticity plays a prominent role in shaping human genetic diversity.