Researchers led by V. Tretyachenko have identified nearly 14,000 protein variants in human tissues, expanding understanding of the human functional proteome. The study, published in *Nature*, examined proteogenomic data from 29 healthy human tissues and revealed 13,910 confidently localized variants representing 7,215 unique single amino acid substitutions alongside corresponding reference proteoforms.
The abundance of both genetic variants – including single nucleotide polymorphisms (SNPs) and somatic mutations – and mistranslated protein variants correlated with their allele frequencies in the human population. The research demonstrates that non-genetic substitutions offer a distinct pathway for exploring protein sequence space, bypassing constraints of the genetic code. Experimental validation confirmed these non-genetic substitutions on purified proteins.
Analysis of cancer-derived cell lines revealed specific and recurring non-genetic variation patterns during amino acid starvation. Hundreds of substituted non-genetic proteoforms were consistently found in multiple healthy individuals or mapped to annotated protein functional sites. Researchers propose these substitutions represent a novel class of functional protein phenotypic variants, indicating that non-genetic amino acid substitutions significantly expand the functional proteome.
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