A major goal in biology is to map entire proteomes to better understand the biology and evolution of cells. However, our current views of proteomes are conservative and biased against small proteins. Besides serendipitous discoveries of small proteins, it has been largely assumed that eukaryotic mature mRNAs contain a single ORF and that non-coding RNAs are not translated because their ORFs are too short to play a functional role. A flurry of recent studies brought to light an unexplored proteome that is mainly translated from short ORFs in non-coding regions and from alternative ORFs (AltORFs) in reference genes. The detection of these small proteins and the elucidation of their functions remain challenging and open a new dimension of eukaryotic proteomes, including the birth of novel genes and proteins.
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