On the unknown proteins of eukaryotic proteomes

TL;DR

This study analyzes unknown proteins across diverse eukaryotic proteomes, revealing that many are species-specific, poorly predicted by structure models, and that singleton counts vary with evolutionary distance, especially in metazoans.

Contribution

It establishes a large-scale reference system for eukaryotic proteomes and uncovers patterns in unknown proteins and their evolution across different lineages.

Findings

Most singletons are not known at the protein level.

AlphaFold2 predictions for singletons are generally poor.

Singleton counts increase with evolutionary distance in metazoans.

Abstract

In order to study unknown proteins on a large scale, a reference system has been set up for the three major eukaryotic lineages, built with 36 proteomes as taxonomically diverse as possible. Proteins from 362 eukaryotic proteomes with no known homologue in this set were then analyzed, focusing noteworthy on singletons, that is, on unknown proteins with no known homologue in their own proteome. Consistently, according to Uniprot, for a given species, no more than 12% of the singletons thus found are known at the protein level. Also, since they rely on the information found in the alignment of homologous sequences, predictions of AlphaFold2 for their tridimensional structure are usually poor. In the case of metazoan species, the number of singletons seems to increase as a function of the evolutionary distance from the reference system. Interestingly, no such trend is found in the cases of viridiplantae and fungi, as if the timescale on which singletons are added to proteomes were different in metazoa and in other eukaryotic kingdoms. In order to confirm this phenomenon, further studies of proteomes closer to those of the reference system are however needed.