Encoded and non-genetic protein variants expand human functional proteome.

Non-genetic amino acid substitutions significantly expand the human proteome, with 13,910 variants identified across 29 tissues, revealing a new layer of proteome diversity.

• Why it matters: Understanding the full scope of proteome variation is crucial for insights into human biology and disease, yet current methods lack the ability to detect and evaluate non-genetic protein variants.
• What they did: Analyzing a large-scale proteogenomic dataset, the study identified thousands of variants, validated non-genetic substitutions experimentally, and examined their patterns in healthy and cancer cells.
• The result: Non-genetic substitutions are recurrent, functionally relevant, and mirror population allele frequencies, suggesting they form a novel class of functional protein variants that expand the human proteome.