Genome complexity: must study the unknome (Introduction)

by David Turell , Friday, March 08, 2024, 18:42 (50 days ago) @ David Turell

The unknome refers to the massive gap in our knowledge about all genes:

https://www.the-scientist.com/stepping-into-the-unknome-71706

"To encourage research on these many mystery genes, a team of scientists have created a new publicly available database that ranks genes based on how little is known about them.3 Using this new directory, they selected more than 200 neglected genes that are evolutionarily conserved between fruit flies and humans. The systematic silencing of these genes in fruit flies revealed that many are essential for survival and other important biological functions, demonstrating that there is still much to be explored in the vast unknowns in the genome.

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“'There's still a couple thousand genes in the human genome, at least, for which essentially nothing is known, and then there are some where a little is known, but not very much,” said Munro.

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“'Quite often we'd turn out proteins, or other people would find proteins, which are very well conserved in evolution, but absolutely nothing is known about them,” said Munro.

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"An initial screen revealed that nearly 25 percent of the unknown genes were essential for survival. “The Drosophila geneticists found that quite surprising as they sort of assumed that everything important had been found by conventional genetic screens in flies,” said Munro.

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"They found that many of these genes contributed to male and female fertility, wing growth, aberrant protein removal, locomotion, and resilience to stress. One gene, CG11103—called TM2 domain containing 2 (TM2D2) in humans—surprised Munro and his team. When they deleted the gene in female flies, any eggs they laid failed to develop. They linked this failure to launch to an overproduction of cells in the offsprings’ nervous systems, a phenotype that indicates defects in the conserved and highly studied Notch signaling pathway. “Despite all the work that's been done on [the Notch signaling pathway], this gene had not been found,” said Munro.

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"Previous research by Stoeger revealed that scientists continue to focus their research on a minority of known genes identified before the Human Genome Project. In a recent study, Stoeger and his team examined where in the -omics analysis pipeline these understudied genes leak out and found that scientists tend to abandon them while writing up the results, instead drawing attention to known, popular genes.

"The availability and reliability of reagents is another rate-limiting step, as is convincing researchers to step into the unknome. “It is risky,” said Munro. “It's something where you have to have a very good reason or a good clue to take on something like this, because it is very challenging.” Additionally, funding bodies tend to be risk averse when doling out the dough for research, but Munro said that he has spoken with a couple of organizations that are considering funding research into the unknome to address this problem.

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"Beyond its potential value in guiding scientists towards neglected proteins, the Unknome database also highlights just how much of biology remains to be explored. Looking to the future, Munro is excited to see what new tools, like the Unknome database, help reveal. “There might be things out there which are like the unknowns,” said Munro. “No one's looking for the components because no one knows the biological process exists yet. That may sound a bit fanciful, but there are a few examples.” CRISPR was hiding in plain sight in Escherichia coli, leaving scientists like Munro to wonder what else is out there."

Comment: everything in the genome must mean something. There is/was purpose at work in creating it. This paper outlines the difficulties research groups face. But the rewards like CRISPR are worth the new efforts. We can code DNA for a number of genetic diseases now with more undoubtedly coming. Please remember we are using living material while not knowing the big black box, which is how genes accomplish their business. God remains one step ahead of us.