Evolution and humans: how our small gene number works (Evolution)

by David Turell , Thursday, February 15, 2024, 00:58 (72 days ago) @ David Turell

So many repeats:

https://www.quantamagazine.org/a-lobby-where-a-molecule-mob-tells-genes-what-to-do-2024...

"the human genome is rich in regulatory connections. Our genes interact in a dense network, in which pieces of DNA and the molecules they encode (RNA and proteins) control the “expression” of other genes, influencing whether they make their respective RNA and proteins. To understand the human genome, we needed to understand this process of gene regulation.

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"gene regulation... involves a gang of molecules, including proteins, RNAs and pieces of DNA from throughout a chromosome, that somehow collaborate to control the expression of a gene.

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"have uncovered a component of this fuzzy mode of gene regulation. Their work, published last September in Science, suggests that the DNA near a gene acts as a kind of shallow well for trapping diverse regulatory molecules, keeping them ready for action so that, when needed, they can add their voice to the decision about whether to activate the gene.

"These regulatory wells are made from decidedly odd stretches of DNA. They consist of sequences in which a short stretch of DNA, from one to six base pairs long, repeats many times over. Tens of copies of these “short tandem repeats” (STRs) can be strung together in these sequences, like the same little “word” written again and again. (my bold)

"STRs are abundant in the human genome: They comprise about 5% of all our DNA. They were once thought to be classic examples of “junk” DNA because a repetitive DNA “text” made up only of STRs can’t hold nearly as much meaningful information as, say, the irregular sequence of letters that make up a sentence in this article.

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"In humans and other eukaryotes, the regulatory sequences can be more numerous, various — and perplexing. Regions called enhancers, for example, affect the probability that a gene will be transcribed. Enhancers are often the targets for proteins called transcription factors, which can bind to boost or inhibit gene expression. Weirdly, some enhancers are tens of thousands of base pairs away from the genes they regulate, and are only brought close to them through the physical rearrangement of the loops of DNA in a packed chromosome.

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“Traditionally in genomics, the goal has been to classify genomic sites in a [binary] way as either ‘bound’ or ‘unbound’” by transcription factors, Fordyce said. “But the picture is way more nuanced than that.” The individual members of those gene regulatory “committees” don’t seem to be invariably present for or absent from their meetings, but rather have different probabilities of being there or not.

"The tendency of gene regulation in eukaryotes to rely on so many diverse weak interactions among large molecular complexes “is one of the things that makes it notoriously difficult to get a handle on theoretically,” said the biophysicist Thomas Kuhlman ... It’s a profound puzzle how, out of this seemingly chaotic process, precise decisions about turning genes on and off emerge.

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"Molecules generally move around the cell by diffusion, buffeted by all the other surrounding molecules, such as water, and wandering in random directions. We might expect these loose committees to drift apart too quickly to do their regulatory job.

"That, Fordyce and her colleagues think, is where the STRs come in. STRs are strikingly common within enhancer sites on DNA. In their paper, the researchers argue that the STRs act as sticky patches that convene transcription factors and stop them from straying.

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"The Stanford team found that different STR sequences can alter the binding affinities of transcription factors to DNA by as much as a factor of 70; they sometimes have more impact on transcription factor binding than changing the sequence of the binding motif itself. And the effects were different for the two different transcription factors they looked at.

So STRs seem able to fine-tune the ability of transcription factors to dock at a DNA site and thus to regulate a gene. But how, exactly?

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“'There are now multiple examples that support the idea that DNA elements can crowd transcription factors to the point where they form condensates with cofactors,” said Richard Young, a cell biologist ... Enhancers bind many transcription factors to produce that crowding. STRs may be an ingredient that helps muster transcription factors to cluster near a gene, but they won’t be the whole story.

"Why regulate genes in this complicated manner, rather than relying on the kind of strong and specific interactions between regulatory proteins and DNA sites that dominate in prokaryotes? It’s possible that such fuzziness is what made large complex metazoans possible at all.

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"To Fordyce, it suggests that STRs “may therefore serve as the raw material for evolving new regulatory elements and fine-tuning existing regulatory modules for sensitive transcriptional programs,” such as those governing the development of animals and plants.

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“The gene regulatory systems in bacteria and eukaryotes do seem to have diverged quite substantially,” Tjian agreed."

Comment: human gene fuzziness gives many more results the rigidity of bacterial DNA controls.