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Natural Selection Shapes Codon Usage in the Human Genome.


ABSTRACT: Synonymous codon usage has been identified as a determinant of translational efficiency and mRNA stability in model organisms and human cell lines. However, whether natural selection shapes human codon content to optimize translation efficiency is unclear. Furthermore, aside from those that affect splicing, synonymous mutations are typically ignored as potential contributors to disease. Using genetic sequencing data from nearly 200,000 individuals, we uncover clear evidence that natural selection optimizes codon content in the human genome. In deriving intolerance metrics to quantify gene-level constraint on synonymous variation, we discover that dosage-sensitive genes, DNA-damage-response genes, and cell-cycle-regulated genes are particularly intolerant to synonymous variation. Notably, we illustrate that reductions in codon optimality in BRCA1 can attenuate its function. Our results reveal that synonymous mutations most likely play an underappreciated role in human variation.

SUBMITTER: Dhindsa RS 

PROVIDER: S-EPMC7332603 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Natural Selection Shapes Codon Usage in the Human Genome.

Dhindsa Ryan S RS   Copeland Brett R BR   Mustoe Anthony M AM   Goldstein David B DB  

American journal of human genetics 20200608 1


Synonymous codon usage has been identified as a determinant of translational efficiency and mRNA stability in model organisms and human cell lines. However, whether natural selection shapes human codon content to optimize translation efficiency is unclear. Furthermore, aside from those that affect splicing, synonymous mutations are typically ignored as potential contributors to disease. Using genetic sequencing data from nearly 200,000 individuals, we uncover clear evidence that natural selectio  ...[more]

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