Genome complexity: a new way of understanding how it works (Introduction)

by David Turell , Friday, July 12, 2024, 18:38 (135 days ago) @ David Turell

From a book, How Life Works:

https://aeon.co/essays/we-need-new-metaphors-that-put-life-at-the-centre-of-biology?utm...

"...at least some of that non-coding genome is now known to be involved in regulating genes: altering, activating or suppressing their transcription into RNA and translation into proteins...So, to understand how life really works at the genomic level, we need to understand gene regulation.

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"At first these non-coding (nc) RNA genes...seemed a mere curiosity. But their numbers have been growing sharply, and now slightly exceed the number of coding genes. Some predict that eventually ncRNA genes will turn out to far outnumber protein-coding genes. The ncRNAs themselves may vary hugely in length, from many hundreds of ‘letters’ to a mere 20 or so. It is not yet known what many of them do, but in general they are thought to play important roles in gene regulation. (my bold)

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"For us, there is layer after layer of regulatory processes, and we have little notion yet of how it all adds up. The same transcription factor can act on several different genes and can have different effects on the same gene in different types of cell, so that the result depends on some higher-level contextual information. Genes are also regulated by how the physical material of the chromosomes called chromatin – a composite of DNA with attached proteins called histones – is packaged up, which is a poorly understood matter. It’s as though some parts of the genome get filed away where they can’t be read. (my bold)

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"What’s more, our genes tend to be regulated not by individual molecules but by whole gangs of them. Transcription factors act together with other molecules (especially that regulatory ncRNA) and with regulatory segments of DNA called enhancers, insulators and so on, in vast teams that gather into loose collectives that some call condensates, which emerge like blobs of vinegar in the oil of salad dressing. No one knows how all this works,...

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"...it’s not hard to see why, the more complex the organism, the fuzzier its molecular mechanisms have to be. A huge machine that works only if all its countless components interlock in precisely coordinated ways is far too fragile – especially if those parts are, like molecules, constantly moving about randomly in a warm, wet environment. By the same token, if life relied on the accurate readout of innumerable genomic instructions in exactly the right order, it would be far too vulnerable to errors. It’s for these reasons that we are not machines – not, that is, like any machine humans have ever built. It’s a far better and more robust solution to find principles that work over many hierarchical levels, with the operation at one level being not too sensitive to the fine details of the levels below. Gene regulation by rather loosely defined condensates rather than by specific molecular switches, say, means that it can still work without every molecule having to be present and correct. (my bold)

"Evolution has, to speak anthropomorphically, evidently ‘designed’ our molecules to work in this fuzzy way. In contrast to the lock-and-key principle by which protein enzymes were long thought to recognise and transform their target molecules, some of the most important proteins in our cells, including many transcription factors, have shapes that are only loosely defined, enabling them to stick to others without being too choosy about it. And those little regulatory RNAs are generally too small to carry enough information for their unions to be very selective; they too work collectively, arriving at a decision, as it were, by committee.

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"...the true causes of outcomes at the level of traits and of health don’t all come from the bottom up, from the genes, but emerge at all levels in the hierarchy of scales. That’s how life works.

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"...I discovered to what a considerable extent some important biological molecules don’t necessarily choose their binding partners with exquisite and tight selectivity, but on the contrary are highly promiscuous and form only very transient and weak partnerships. There I learnt how cells of a given type don’t all make identical suites of biomolecules, and how we can quantify their variety.

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" Our biomolecules appear to make decisions not in the manner of on/off switches but in loosely defined committees that obey a combinatorial logic, comparable to the way different combinations of just a few light-sensitive cells or olfactory receptor molecules can generate countless sensations of colour or smell.

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"And shouldn’t we have seen that all along? For what, after all, is extraordinary – and challenging to scientific description – about living matter is not its molecules but its aliveness, its agency.

Comment: this article describes the surprised reaction at the degree of complexity, the multi-layer of controls, as if we never escaped the Darwinian approach of cells as blobs. We can now see them as "Barbara McClintock in recognising that the genome is a responsive, reactive system, not some passive data bank: as McClintock called it, a ‘highly sensitive organ of the cell’". So, it is a swarm of regulating ncRNA's in loose control that works! Yes, surprising and highly suggests a designer at work.