@zachary-ardern.bsky.social and myself suggested just that hypothesis in our commentary on a yeast paper from the @carvunis.bsky.social lab—I don't think this has been tested yet!

Generally, I think by "non-functional" people mean "when you knock out that one protein, it doesn't affect fitness"

But I guess if the goal is to fill in gaps in annotation for less studied organisms, mass spec can be of some help. Here's a sampling of proteogenomics-based studies that makes the general point.

(Table from the same paper) (4/4)

In cases where people have tried to validate RiboSeq-supported non-annotated proteins with mass spec in the same study—generally, very few could be confirmed.

See the highlighted rows from the table below, taken from our recent review paper: genome.cshlp.org/content/earl... (3/4)

Similar conclusions have previously been reached by Fijalkowski et al (2021), and for eukaryotes, Wacholder & Carvunis @carvunis.bsky.social (2023).

These proteins are either way too small, or not expressed enough, or generate "bad" (hard to detect) peptides—mass spec doesn't like them. (2/4)

We also caught such events of novel expression "in the act": i.e., in the context of experimental evolution.

Bacterial systems provide the opportunity to track fine-grained steps in gene emergence, step-by-step.

Read the paper here -

journals.plos.org/plosbiology/...

...How inert, non-expressed parts of the genomes can gain expression.

This proposed first step of gene birth has been studied extensively in bacteria, with no sign of stopping—see attached table for a sampling.

In our previous work... (6/7)

If you couldn't tell, these hypotheses are essentially unfalsifiable!

(In a manuscript currently under review, we propose a novel approach to possibly crack this dilemma)

But we also point to other, more fruitful avenues to direct new gene research in bacteria.

E.g.: (5/7)

...This question is impossible to settle!

At least, based on how the two theories and their predictions have been set up:

The "native" origin: Orphan genes evolve so fast that homology gets lost;

While "foreign" origin: They're from sources we haven't sampled yet. (4/7)

One, they're highly diverged versions of coding or non-coding sequences already "native" to the genome,

Two, they're "foreign" genes—deposited in their current habitats from sources unknown.

We review the evidence for and against these hypotheses, and conclude... (3/7)

Standard modes of thinking about gene birth—duplication via divergence—don't really apply to "orphan genes", which lack homologs.

What's more, gene birth via duplication isn't even common in bacteria.

So where did these genes come from?

Literature proposes two answers. (2/7)

Thanks so much boss!

@idanfrumkin.bsky.social (why can't I tag you?)