Tuesday, May 14, 2019

Peak Gene

Interesting article.

We have reached peak gene, and passed it.
Ken Richardson in "It's The End Of The Gene As We Know It" 

In scientific, as well as popular descriptions today, genes “act,” “behave,” “direct,” “control,” “design,” “influence,” have “effects,” are “responsible for,” are “selfish,” and so on, as if minds of their own with designs and intentions.

But at the same time, a counter-narrative is building, not from the media but from inside science itself.... Scientists now understand that the information in the DNA code can only serve as a template for a protein. It cannot possibly serve as instructions for the more complex task of putting the proteins together into a fully functioning being, no more than the characters on a typewriter can produce a story.
...
First, laboratory experiments have shown how living forms probably flourished as “molecular soups” long before genes existed. They self-organized, synthesized polymers (like RNA and DNA), adapted, and reproduced through interactions among hundreds of components. That means they followed “instructions” arising from relations between components, according to current conditions, with no overall controller: compositional information, as the geneticist Doron Lancet calls it.
In this perspective, the genes evolved later, as products of prior systems, not as the original designers and controllers of them. More likely as templates for components as and when needed: a kind of facility for “just in time” supply of parts needed on a recurring basis.
...
We have traditionally thought of cell contents as servants to the DNA instructions. But, as the British biologist Denis Noble insists in an interview with the writer Suzan Mazur, “The modern synthesis has got causality in biology wrong … DNA on its own does absolutely nothing until activated by the rest of the system … DNA is not a cause in an active sense. I think it is better described as a passive data base which is used by the organism to enable it to make the proteins that it requires.”

PS: the proposed definition of "gene" by Portin and Wilkins:
A gene is a DNA sequence (whose component segments do not necessarily need to be physically contiguous) that specifies one or more sequence-related RNAs/proteins that are both evoked by Genetic Regulatory Networks and participate as elements in Genetic Regulatory Networks, often with indirect effects, or as outputs of Genetic Regulatory Networks, the latter yielding more direct phenotypic effects.
Wiki tells us: genetic regulatory network (GRN) is a collection of molecular regulators that interact with each other and with other substances in the cell to govern the gene expressionlevels of mRNA and proteins.  

Comments (11)

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I'm not impressed by the author's extravagant claims about "peak gene". He rounds up a bunch of old and new discoveries about how genes function and tries to make it sound like these undermine the fundamental importance of genes - they don't, though they do show how intricate their function is in living things. The proper analogy for a gene is not a master or ruler, but a program. By itself, a computer program is inert and useless, like a gene without a cell. Some components of a cell resemble the bootstrap loaders and assemblers that implement programs in computers.

The fertilized egg that becomes human, mouse, or oak tree comes with a set of such mini programs, implemented in proteins and RNA, but they can't make more of themselves, because their blueprints are in the DNA. Only by using the DNA to make more of these and other cellular components can cells grow, divide, differentiate and form organisms.

So DNA is like a program, only it's a very special program, since it also contains instructions for making more computers, and not only the computers but the whole range of components needed to supply the computer with power and other essentials.

Perhaps the most outrageously nonsensical claim in the article is that genetically identical animals exhibit the full range of variability of the wild types. That is simply and utterly false. On the other hand, they aren't truly identical, because there is many a mutation between egg and fully developed organism. For example, the cells in your brain don't contain exactly the same DNA as the egg from which they originate. They will probably have about 1000 point mutations, or variant SNPs, from that egg and each other that occurred in the process of cell division growth and migration that formed your brain.

Incidentally, SNPs (single nucleotide polymorphisms) are just one of the many ways DNA strands can vary. There are also gene duplications, inversions, copy number variants, and many other variations. So SNPs are just a little of the way genomes can differ.
3 replies · active 307 weeks ago
The proper analogy for a gene is not a master or ruler, but a program. By itself, a computer program is inert and useless, like a gene without a cell. Some components of a cell resemble the bootstrap loaders and assemblers that implement programs in computers.

Aha! my take-away analogy was that genes are like the persistent store - say the database - in a computer program. The database provides information needed to construct in-memory data structures and objects, but is not the program, nor the loaders or assemblies - those are in the rest of the cell.

Perhaps the most outrageously nonsensical claim in the article is that genetically identical animals exhibit the full range of variability of the wild types. That is simply and utterly false. On the other hand, they aren't truly identical, because there is many a mutation between egg and fully developed organism. For example, the cells in your brain don't contain exactly the same DNA as the egg from which they originate. They will probably have about 1000 point mutations, or variant SNPs, from that egg and each other that occurred in the process of cell division growth and migration that formed your brain.

The SNPs aren't expressed in proteins or regulating RNA, so that is quite irrelevant. The question is the truth of this: "Conversely, it is now well known that a group of genetically identical individuals, reared in identical environments—as in pure-bred laboratory animals—do not become identical adults. Rather, they develop to exhibit the full range of bodily and functional variations found in normal, genetically-variable, groups." Yes, it seems over the top. But here's the J. Freund paper he referred to: https://pure.mpg.de/rest/items/item_2098536/compo...
Here's another: https://academic.oup.com/hmg/article/14/suppl_1/R...

"This list is far from comprehensive and is meant to illustrate our point that significant phenotypic variation, including crossing a threshold to fatal disease, can emerge from animals that have an identical, cloned genetic background, and frequently-occurring differences in mitochondrial DNA cannot be a universal mechanism for a wide spectrum of phenotypic differences. "
This article is quite interesting, and speculates that the differences observed are due to epigenetics. Epigenetic factors consist modifications of the DNA or the associated chromatin that affect the subsequent expression of that DNA. In my program analogy, these can be thought of as flags built into the program code. These epigenetic factors can (sometimes) persist across generations but they are also known to undergo dramatic modifications during development and subsequently. For example, what makes one cell a neuron and another a skin cell is partly controlled by epigenetic factors, some of which are being reset very early in development. For example, it's possible, the authors speculate that when the four or eight cell clumps that separate to form monozygotic twins, cells in one part of the clump have already had some of their epigenetic flags set to something other than those in the other clump.

When a somatic cell is reprogrammed to become a zygote in cloning, the reprogramming consists of essentially of resetting the epigenetic flags to a starting configuration. This resetting process may well be imperfect, resulting in developmental failures in the clone.
The SNPs aren't expressed in proteins or regulating RNA

That is not true in general. A SNP is the change in any base pair in the genome. SNPs in genes or regulatory regions are the most interesting ones and the most often tested for. SNPs in genes may be synonymous, nonsynonymous, or frame disrupting. Synonymous changes don't change the coded for amino acid and usually (but not invariably) don't have physiological consequences, nonsynonymous changes change the amino acid and the protein. Frame changing (also called nonsense) SNPs usually abolish the produced protein. Sickle cell anemia is usually produced by a single SNP. So are most other genetic diseases.

Rather, they develop to exhibit the full range of bodily and functional variations found in normal, genetically-variable, groups. Not over the top - categorically false. I've read the cited paper and can find no place where it makes such a claim. What it does find is behavioral plasticity - mouse brains, like human brains, learn from their experiences. Also, at least some learning is associated with post developmental neurogenesis.

Finally, programs are data (at least in the von Neumann paradigm), but not all data consists of programs. Genes are instructions which when implemented result in the production of RNA and (in the case of mRNA) proteins. All those other components of the cell (RNA, proteins, membranes) are coded for, directly or indirectly, by the genes.
4 replies · active 307 weeks ago
Yes, but you wrote " They will probably have about 1000 point mutations, or variant SNPs, from that egg and each other that occurred in the process of cell division growth and migration that formed your brain" -- but I don't think there are 1000 variants of a protein in my brain, and whether that has any significance. Because otherwise, by your argument, every cell in the Nth generation after the germ cell is producing variant proteins, and germ-cell-genetically-identical multicellular organisms will have huge variations.
About 1.5% of the genome consists of genes, so maybe 15 of those 1000 might be in genes. Of course many of those genes would be turned off in the brain so wouldn't matter, but there are probably a few mutant neurons in a typical brain, which might give rise to some differences between identical twins. I think, but am not sure, that the 1000 number is based on the total number of variants found in a bunch of neurons, so the chance of any individual neuron having a deleterious gene that wasn't inherited might be small.

Slightly off topic, but FOXP2 is a famous gene, active in the brain and elsewhere. It differs in exactly two SNPs from the version found in other great apes. Another additional SNP in FOXP2 seriously disrupts human language. The protein it produces is purely regulatory - it modifies the amount of expression of other genes. Most of the genes active in the human brain that differ from the versions found in other great apes are regulatory genes. So our brains, which are three or more times larger than those of the other great apes, differ almost entirely in being retuned - like a race car engine. Completely novel proteins are very rare in the human brain.
...huge variations There are about forty trillion cells in the human body, so the minimum number of divisions to produce that many is about 45. Each division produces about a 1 in ten billion chance of changing a given base pair, of which there are about 3 billion in a human body. So if my math is right, at least 75% of cells should have mutation. Most of those will occur in non-coding regions and others will be neutral - not change a protein. Seriously deleterious mutations in any line will terminate it by death of the cell. But some will survive and can produce weird effects, one of the simplest of which is the calico type patterns seen in some cats and horses.

You might be interested in the book: "She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity" by Carl Zimmer. It's better at explaining many things than most of the genetics textbooks I have read.
I should say that the calico patterns are almost invariably produced by epigenetic changes rather than actual mutations. The paired chromosomes each have an allele for different color, one of which is turned on in some parts of the skin and the other is turned on in the others.
Anyway, do you agree with this:

"A gene is a DNA sequence (whose component segments do not necessarily need to be physically contiguous) that specifies one or more sequence-related RNAs/proteins that are both evoked by Genetic Regulatory Networks and participate as elements in Genetic Regulatory Networks, often with indirect effects, or as outputs of Genetic Regulatory Networks, the latter yielding more direct phenotypic effects."
Yes indeed.

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