title: Translational plasticity facilitates the accumulation of nonsense genetic variants in the human population.
abstract: Genetic variants that disrupt protein-coding DNA are ubiquitous in the human population, with about 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.
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.|Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.|Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Jagannathan
authors.affiliation: Computational Biology Program, Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.|Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Bradley
mesh_terms: D000066670:Cell Plasticity; D018389:Codon, Nonsense; D018388:Codon, Terminator; D056084:Genetic Fitness; D015894:Genome, Human; D023281:Genomics / Q000379:methods*; D006801:Humans; D000073658:Loss of Function Mutation; D014176:Protein Biosynthesis; D040901:Proteomics / Q000379:methods*
chemical_list: D018389:Codon, Nonsense; D018388:Codon, Terminator