The inconvenient truth about genetics

[CharonY]

46 minutes ago, John Cuthber said:

YOu seem to want the word "egg" bolded.OK, whatever floats your boat.

Now, what part of an egg isn't made from proteins and stuff that are coded in DNA?

And the really cool thing is that the DNA codes for the machinery that reads the DNA.
It's such a neat idea that people even tried to copy it.

https://en.wikipedia.org/wiki/RepRap_project

It's good to see that you agree that the lipids and stuff are also all controlled by the DNA, albeit indirectly.

 

I'm still waiting for someone to answer my question.

If the data's not in the DNA, where is it? (for extra credit, how is it encoded and transmitted to the next generation?)

 

 

I think you are just seeing the same issue from different perspectives. The DNA encodes required proteins (though again, it does not encode the required metabolites, such as nucleotides, amino acids etc, though it does encode the machinery involved in acquiring and synthesizing it), but it requires the presence of a fully functional cell background (with the machinery in place) to produce them. This is the chicken or egg problem as as without everything already provided by the cell (or having an incompatible cellular set up) the program will stall. Likewise, not providing required nutrient will inhibit the production of said machinery. I.e. if you nitrogen (or phosphate) limitation, translation/transcription will not proceed and it does not matter that the genome has all the information to produce all the proteins required for nitrogen/phosphate uptake.

Plus there is increasing awareness that the cellular content plays an important role in the trajectory of cells, which might play an important role in asymmetric cellular aging. I.e. depending on what cellular component each daughter cell inherits (as the content is not necessarily divided perfectly equally), they may have different growth trajectories. So despite the fact that both cells inherit the same DNA, one may remain highly active, whereas the other one gets all the crap and heads to apoptosis.

So yes, the basic genetic material is without doubt present and inherited within the DNA. However, its expression and the translation into a given phenotype is highly dependent on the intracellular (and extracellular) content.

[Ken Fabian]

Seems like there is a crossover period during the earliest stages of fertilisation where the new DNA operates within structures it had no part in making. The egg and the cell 'machinery' it contains came before the new mix of X's and Y's and is a product of parental DNA. That 'new' DNA only functions (at first) within existing biological structures of other's making  - it doesn't make them it'self. Not sure to what extent epigenetic guidance and triggering is provided via the ova a sperm - but expect that those will be at work. At some later stage it will make those for kickstarting the next generation

4 hours ago, DanielBoyd said:

My proposed alternative to genetic design is not some other form of design but self-assembly.

I think that is more like what it actually is - and naming it 'genetic design' always was potentially misleading. Analogy breaks down.  The shape of a body part is the consequence of the self-assembly - no specifications for it's shape exist, but as processes of cell divisions and differentiation and growth occur, that shape is where the growth limits are reached. If it doesn't work the individual is in trouble and is unlikely to survive to reproduce - but the evolutionary process has left us with the  ones that work.

Picking just one point out of the many -

On 6/23/2019 at 5:27 AM, DanielBoyd said:

After a protein has been constructed on the basis of genetic information, it therefore needs to go to the right place in the cell and join up with other molecules in order to play its part. The genome has no information or mechanism to guide it. 

I would expect diffusion to be a principle means for getting specific molecules to the right place within a cell  - the 'right place' will be taking up those molecules and concentrations will be lower around there, so molecules will flow from where they are higher concentration to lower. Over such short distances, diffusion will have a strong affect. It would require a minimum concentration of those molecules - more than end up being used, with lots left over, to be recycled into other things.

[zapatos]

2 hours ago, Ken Fabian said:

I would expect diffusion to be a principle means for getting specific molecules to the right place within a cell  - the 'right place' will be taking up those molecules and concentrations will be lower around there, so molecules will flow from where they are higher concentration to lower. Over such short distances, diffusion will have a strong affect. It would require a minimum concentration of those molecules - more than end up being used, with lots left over, to be recycled into other things.

Great point. My understanding is that thermal energy primarily what moves things around in a cell, and they move very fast.

I don't know how good this source is but it is line what I had previously understood to be true.

Quote

You may wonder how things get around inside cells if they are so crowded. It turns out that molecules move unimaginably quickly due to thermal motion. A small molecule such as glucose is cruising around a cell at about 250 miles per hour, while a large protein molecule is moving at 20 miles per hour. Note that these are actual speeds inside the cell, not scaled-up speeds...

Because cells are so crowded, molecules can't get very far without colliding with something. In fact, a molecule will collide with something billions of times a second and bounce off in a different direction. Because of this, molecules are doing a random walk through the cell and diffusing all around. A small molecule can get from one side of a cell to the other in 1/5 of a second.

As a result of all this random motion, a typical enzyme can collide with something to react with 500,000 times every second. Watching the video, you might wonder how the different pieces just happen to move to the right place. In reality, they are covering so much ground in the cell so fast that they will be in the "right place" very frequently just by chance.

http://www.righto.com/2011/07/cells-are-very-fast-and-crowded-places.html

[Ken Fabian]

7 minutes ago, zapatos said:

My understanding is that thermal energy primarily what moves things around in a cell, and they move very fast.

I think that is diffusion - the molecular motions diffusion rely upon are thermally driven - Brownian motion iirc. I admit I am a bit vague on the physical mechanisms that make diffusion work, whereby the same kind of molecule seems to be 'repelled' by close proximity but are not affected by presence of other kinds of molecules. Of course there are physical structures that can aid movement - eg microtubules within cells that molecular motors can use to move an attached vesicle or carry signalling molecules-

 

 

Just for the sheer wonder of it - an animation of a molecular motor hauling a vesicle along a micro-tubule -

 

[DanielBoyd]

23 hours ago, Curious layman said:

Eise, you said you only taught for a short time. Wrong. You still do.

And that is a compliment (in my book)

[Curious layman]

1 hour ago, DanielBoyd said:

And that is a compliment (in my book)

Thank you. And that discussion above (and below) is one of the best lessons about genetics I've had. Very interesting I think.

Especially the molecular motor.

Edited June 26, 2019 by Curious layman

[DanielBoyd]

This is quite wonderful: the examples of cellular processes and structures being presented all demonstrated the 'incompleteness' of genetic information as a determining explanation for the functional cell.

With respect to Brownian motion, certainly this may (partly) solve the 'transport problem' of how to move proteins from where they are made to some other place in the cell, but the cell is far from a mixed bag of molecules all zipping around randomly and bumping into each other. It contains many stable structures (usually built out of lipid membranes with specific proteins embedded in them). So getting (and keeping) proteins and other molecules in the right place is essential (and, of course, not genetically determined).

It may have occured to you that up to now, we are still inside the cell: the molecular environment in which the genome still plays a fairly direct and dominant role. Even here, we are encountering the importance of self-assembly in addition to genetic information to get things done. The original article, however,  is primarily about the (massive!) step to the next level of organisation: that of the cellular differentiation and organisation involved in creating a multicellular organism. 

What are your ideas on the relationship between genetic information and. say, the structure of the kidney, of the layers of cells that make up skin tissue?

[Dagl1]

Just now, DanielBoyd said:

This is quite wonderful: the examples of cellular processes and structures being presented all demonstrated the 'incompleteness' of genetic information as a determining explanation for the functional cell.

With respect to Brownian motion, certainly this may (partly) solve the 'transport problem' of how to move proteins from where they are made to some other place in the cell, but the cell is far from a mixed bag of molecules all zipping around randomly and bumping into each other. It contains many stable structures (usually built out of lipid membranes with specific proteins embedded in them). So getting (and keeping) proteins and other molecules in the right place is essential (and, of course, not genetically determined).

It may have occured to you that up to now, we are still inside the cell: the molecular environment in which the genome still plays a fairly direct and dominant role. Even here, we are encountering the importance of self-assembly in addition to genetic information to get things done. The original article, however,  is primarily about the (massive!) step to the next level of organisation: that of the cellular differentiation and organisation involved in creating a multicellular organism. 

What are your ideas on the relationship between genetic information and. say, the structure of the kidney, of the layers of cells that make up skin tissue?

You keep making the assertion that the place where specific proteins go is not genetically determined, but if it is not genetically determined by what is it? Also again, in my first post I mentioned that there are signalling domains such as the nuclear localization signal, that is literally encoded within the genome. Of course you need proteins, made by the genome, to then transport them to the right places but either way that is encoded in the genome. 

If you say that proteins go to specific places based on self-assembly (thus a specific protein with a specific amino acid code will end up at a specific place, then that too is based on the genome isn't it? you can call it self-assembly, but if it would be a different protein, then it wouldn't go the same place due to self assembly, thus it is based on the genome, no?)

For your last point; developmental/proliferation "programs" encoded in the genome lead to the growth and differentiation of specific organs (see my first post for such examples. Look up Sonic Hedgehog if you want an example of hand differentiation, Hox genes for the arms and legs etc), oh here is a thing for how the vertebrae are differentiated and why it isn't 1 entire long bone structure (look up FGF RA differentiation front for more info).

-Dagl

 

[Strange]

57 minutes ago, Dagl1 said:

You keep making the assertion that the place where specific proteins go is not genetically determined, but if it is not genetically determined by what is it? Also again, in my first post I mentioned that there are signalling domains such as the nuclear localization signal, that is literally encoded within the genome. Of course you need proteins, made by the genome, to then transport them to the right places but either way that is encoded in the genome. 

If you say that proteins go to specific places based on self-assembly (thus a specific protein with a specific amino acid code will end up at a specific place, then that too is based on the genome isn't it? you can call it self-assembly, but if it would be a different protein, then it wouldn't go the same place due to self assembly, thus it is based on the genome, no?)

I am really torn here between thinking the OP is stating the obvious (of course genes don’t directly tell proteins where to go) or dismissing the role of genes (obviously the genome says how to create proteins that organise themselves, and cells that differentiate to create  organisms). And obviously the genome can’t do anything without the support of the cell. But the cell is defined by the genome. 

[Dagl1]

44 minutes ago, Strange said:

I am really torn here between thinking the OP is stating the obvious (of course genes don’t directly tell proteins where to go) or dismissing the role of genes (obviously the genome says how to create proteins that organise themselves, and cells that differentiate to create  organisms). And obviously the genome can’t do anything without the support of the cell. But the cell is defined by the genome. 

If it is the former, then I suppose we all agree and it doesn't seem to be such an "inconvenient truth", nor a very... new idea, but as OP has mentioned several times that this is a new thing and not just genetics, therefore I think it is the latter of your options;/

[Ken Fabian]

1 hour ago, DanielBoyd said:

the examples of cellular processes and structures being presented all demonstrated the 'incompleteness' of genetic information as a determining explanation for the functional cell

 I don't see how you come to that conclusion. Of course they do not rely solely on proteins -

 

On 6/25/2019 at 4:46 PM, DanielBoyd said:

Of all these components, DNA only has direct control over the proteins.

Not only proteins; RNA transcribed from DNA also gets used directly in some remarkable molecular machines, such as ribosomes - like a molecular scaffolding that can assemble different proteins together into more complex arrangements than proteins alone -

 

[CharonY]

8 hours ago, Strange said:

I am really torn here between thinking the OP is stating the obvious (of course genes don’t directly tell proteins where to go) or dismissing the role of genes (obviously the genome says how to create proteins that organise themselves, and cells that differentiate to create  organisms). And obviously the genome can’t do anything without the support of the cell. But the cell is defined by the genome. 

I think OP is caught up by semantics and thinks that he found something that is not blindingly obvious (and quite a number of the points made in OP are just entirely empty or false statements with no connection to any underlying hypothesis (that I can see). It is well known that the DNA provides merely the potential for a cell to interact with its environment. These interactions result in a given intracellular content that, in turn interacts with the genome to either attain homeostasis, react to perturbations and so on. The only thing that has been new in recent times is the discovery that even at static conditions,  clonal cells in a given population have remarkable diversity in their intracellular content. However, these still fit perfectly the well-known paradigm (that OP shortly acknowledges and then pretty much forgets for the rest of the post) that phenotypes are based on the interaction of the genotype with the environment (which in this case also includes intracellular content). Again, the principle is  nothing new if one has ever opened a basic college-level textbook.

[CharonY]

11 hours ago, DanielBoyd said:

So getting (and keeping) proteins and other molecules in the right place is essential (and, of course, not genetically determined).

While it has been answered, I will add that that the partitioning of proteins and vesicles in cells is heavily genetically determined. Proteins have leader sequences (i.e. encoded by DNA) that help in assigning to the right place (such as directing them to exporters, integrating them into membranes) vesicles are modified by proteins and directed to specific (protein-) machineries that control the trafficking routes and so on. 

[John Cuthber]

22 hours ago, John Cuthber said:

I'm still waiting for someone to answer my question.

If the data's not in the DNA, where is it? (for extra credit, how is it encoded and transmitted to the next generation?)

The OP's contention is

On 6/22/2019 at 8:27 PM, DanielBoyd said:

Reason 1: The genome does not contain enough information. 

 

And, for that to be true the information has to be stored somewhere else. Where is it?
It's tautological to say it's in the proteins etc because the proteins are made according to the DNA blueprint.

Some proteins fold themselves into vitally important configurations- they do that because the sequence - lain down in the DNA means that's the lowest energy state and they "fall" into it.

 

Some proteins need accessory molecules to fold them.

Well guess where the instructions for those accessories are...
 

Saying "There needs to be protein (etc) infrastructure to read the DNA" is true, but irrelevant.

I need eyes to read a book, but it doesn't make them part of the story.

And once we have addressed this one we can go on to the second thing the OP said 
 

On 6/22/2019 at 8:27 PM, DanielBoyd said:

Reason 3: The genome does not determine which of its genes are used and when. 

which isn't much better.
(So called "reason 2" was a repeat of 1)

Edited June 26, 2019 by John Cuthber

[DanielBoyd]

Sorry, people, I come back from my day job and find a whole thread has grown that I have failed to respond to. Gotta earn a living!

I think the general conclusion is that we don't actually disagree that much: the only direct information present in the genome is for the amino acid sequence, but the amino acid sequences determine how the proteins produced behave in the cell. In this way genetic differences indirectly exert some control over the formation and function of cells, and more indirectly on the interactions between cells that lead to the formation of multicellular organisms.

My point - that the genome does not literally contain a design for these things - may seem trivial, but it's surprising how often you still read about 'a gene for this' or 'a gene for that', when in fact what is happening is that a genetic/protein variation is only having an indirect effect on the complex, emergent, self-organizing system it is a part of. A logic similar to putting the wrong size spark plug in your car and claiming to have explained how the engine works when it splutters. 

This is why the discussion of the quantity of information in the genome is relevant. In information theoretical terms, the emergent processes taking place create more information than is present in the genome. This is not just a 'decompression' of hidden content in the genome, or a random expansion, but a highly specific generation of information that is simply not present there. This is where the 'missing information' comes from.

Re-reading my article, and your responses to it, makes me realise not so much that I am wrong or you are wrong, but that I have spectacularly failed to define the issue sufficiently clearly. So now we're like the two knights meeting at a crossroads arguing about whether the statue is silver or gold (if you know the story).

This could partly be explained by the fact that the article was originally longer, more complete and more formal, but I reduced it down and made it a little more playful in the hope of at least getting it read. I think this particular reduction in information didn't help: the emergent processes that followed created a bit of a monster!

What the solution is I'm not sure, but I would like to thank particularly Eise, John, SharonY,  Ken and Dag1 for your feedback (sorry that I didn't get round to responding to your extensive post on the first page). 

 

[John Cuthber]

28 minutes ago, DanielBoyd said:

My point - that the genome does not literally contain a design for these things - may seem trivial, but it's surprising how often you still read about 'a gene for this' or 'a gene for that'

That's two different things.

Yes, people who talk about "a gene for whatever", unless they are using it as shorthand, or where "whatever" is a single protein are wrong.
But, as I keep asking, if the "design" isn't in the genome, where is it?

The link's indirect, but the genes really do make pretty much everything.

[Arete]

4 hours ago, DanielBoyd said:

I think the general conclusion is that we don't actually disagree that much: the only direct information present in the genome is for the amino acid sequence,

I appreciate you've though deeply about this issue - however this is incorrect. 

 

Regulatory genes can, for example, encode silencing mRNA which is used for post-transcriptional regulation of gene expression. 

RNA secondary structure can act to alter gene expression. 

Somatic V(D)J  recombination of existing genes is critical for adaptive immune function. 

There is an entire field of Developmental Genetics which deals with the mechanisms for differential expression during development - and the vast majority are genetically determined. 

 

Ultimately, the genome does a lot more than simply encode proteins, and much of its less obvious function is newly and incompletely understood - the term "junk DNA" was coined in 1972 to describe the 98% of the human genome that does not encode proteins. It wasn't until the 1990's that we started to unravel the function of non-coding DNA, but it does a lot more than we originally thought and were are still in the process of determining its function. 

[DanielBoyd]

5 hours ago, Arete said:

I appreciate you've though deeply about this issue - however this is incorrect. 

 

Regulatory genes can, for example, encode silencing mRNA which is used for post-transcriptional regulation of gene expression. 

RNA secondary structure can act to alter gene expression. 

Somatic V(D)J  recombination of existing genes is critical for adaptive immune function. 

There is an entire field of Developmental Genetics which deals with the mechanisms for differential expression during development - and the vast majority are genetically determined. 

 

Ultimately, the genome does a lot more than simply encode proteins, and much of its less obvious function is newly and incompletely understood - the term "junk DNA" was coined in 1972 to describe the 98% of the human genome that does not encode proteins. It wasn't until the 1990's that we started to unravel the function of non-coding DNA, but it does a lot more than we originally thought and were are still in the process of determining its function. 

Great, now we are getting to the meaty stuff!

Certainly gene activation and transcription is a more complex mechanism than just sticking an amino acid to a codon, with intermediate steps involving RNA. And, absolutely, there are feedback mechanisms involved in activation.

But if we look at how these actually work, things get trickier. Hox genes have an important role in organismal development and are found across the animal kingdom. However, the same genes have different effects in different species https://www.sciencedirect.com/science/article/pii/S0960982206003216 . Does this not show that they are participants in the organisational processes they take part in, rather than determining it's specific outcome, as would be the case if they constituted a determinative design?

[Dagl1]

3 hours ago, DanielBoyd said:

Great, now we are getting to the meaty stuff!

Certainly gene activation and transcription is a more complex mechanism than just sticking an amino acid to a codon, with intermediate steps involving RNA. And, absolutely, there are feedback mechanisms involved in activation.

But if we look at how these actually work, things get trickier. Hox genes have an important role in organismal development and are found across the animal kingdom. However, the same genes have different effects in different species https://www.sciencedirect.com/science/article/pii/S0960982206003216 . Does this not show that they are participants in the organisational processes they take part in, rather than determining it's specific outcome, as would be the case if they constituted a determinative design?

Maybe I missed it but where does it say that these genes are the exact same; they most likely differ in their sequences (although possibly quite conserved), secondly there are other parts of the DNA which are different, so if we have a developmental gene such as HOX, which activates a specific genomic developmental program, and the program is different, then the HOX gene can be the same while having a different effect, no? 

Now you are saying "Does this not show they are participants in the organisational processes they take part in, rather than determining it's specific outcome, as would be the case if they constituted a determinative design". But the genes, encoded by the genome, are participants in organisational processes, and the combination of all of these genes and their regulation of activity (which is encoded by the genome) together forms the organisational processes (thus is encoded by the genome). 

If you would like to say that there is information present that is not stored within the genome, where do you suggest that it is stored?

-Dagl

Edit: After reading the article more, the authors provide several reason who this mechanism would work, so... how does that fit in with your initial statements (or have you changed your opinion about the original post and what you describe there)?

 

Edited June 27, 2019 by Dagl1

[Strange]

16 hours ago, DanielBoyd said:

but it's surprising how often you still read about 'a gene for this' or 'a gene for that'

So this is an argument about popular science writing / journalism, rather than the actual science?

 

[Strange]

17 hours ago, DanielBoyd said:

This is why the discussion of the quantity of information in the genome is relevant. In information theoretical terms, the emergent processes taking place create more information than is present in the genome. This is not just a 'decompression' of hidden content in the genome, or a random expansion, but a highly specific generation of information that is simply not present there. This is where the 'missing information' comes from.

Do you have any evidence for this claim?

How are you defining the quantity of information in the genome? 

Are you taking into account the interactions (direct and indirect) between different parts of the genome? The (changing) physical confirmation of the chromatin complex?

And how are you defining the amount of information required?

And why do think that people are not of emergent phenomena and self-organisation?

[DanielBoyd]

On 6/27/2019 at 1:54 PM, Strange said:

So this is an argument about popular science writing / journalism, rather than the actual science?

 

If only! Typing "A gene for" into Google Scholar produces 245,000 hits. Admittedly, many of these are biochemical studies where there is a direct relationship, but certainly not all. Within the scientific community there is an implicit or explicit assumption that hereditability of traits is synonymous with genetic determinism. Therefore anything that is inherited must be genetically determined. Therefore morphology and physiology are genetically determined. That is the assumption I am challenging with this article.

[Arete]

 

On 6/26/2019 at 10:51 PM, DanielBoyd said:

But if we look at how these actually work, things get trickier. Hox genes have an important role in organismal development and are found across the animal kingdom. However, the same genes have different effects in different species https://www.sciencedirect.com/science/article/pii/S0960982206003216 . Does this not show that they are participants in the organisational processes they take part in, rather than determining it's specific outcome, as would be the case if they constituted a determinative design?

From your own citation: "Evidence in support of this last hypothesis has come from recent studies which document the overlapping function of different Hox genes [18], [19], and comparative studies of expression patterns in a number of crustaceans and insects [13], [14], [20] which support the idea that changes in Hox gene regulation may be responsible for the diversification of body plans and the generation of new segment types."

Substantial research over the last 20 years has elucidated that spatio-temporal variation in Hox gene regulation and protein plasticity allows for an extraordinary array of body plans from the same ancestral set of homeobox genes. e.g.  

"A considerable body of evidence suggests that evolutionary changes in developmental gene regulation have shaped large-scale changes in animal body plans and body parts. In particular, many comparative analyses of Hox gene expression in arthropods, annelids, and vertebrates have revealed a consistent correlation between major differences in axial morphology and differences in the spatial regulation of Hox genes." https://www.cell.com/fulltext/S0092-8674(00)80868-5

https://onlinelibrary.wiley.com/doi/full/10.1002/bies.201600246

 

So, no, it supports the idea that developmental genetics underlies morphological diversity in the animal kingdom. 

 

[Sensei]

On 6/22/2019 at 9:27 PM, DanielBoyd said:

There are, of course, genes that have an effect on development. Meddle with the genes of a fruit fly and you can make legs grow out of their head. Hey presto! But again, let’s not overstate what is happening here. This is not like introducing a new complex feature on the basis of a necessarily equally complex new design. It is simply a matter of causing one of the existing complex features to be in the wrong place. It tells us nothing about how legs are built. 

If you claimed that these genes have only localization of leg, without entire instruction how to make leg, this statement is obviously incorrect and easily verifiable. Gene found in one organism can be attached in laboratory to completely different organism DNA. In your example leg of fruit fly would be growing in animal which has completely no connection to fruit fly. So procedure how to create entire leg must be inside of this code together with localization on body.

It's widely used technique to take genes from plant with natural resistance for some e.g. insects, or with required features, and transferring them to target plants.

 

There are also ways to transfer genes other than inheritance from parents.

https://en.wikipedia.org/wiki/Horizontal_gene_transfer

 

Edited July 1, 2019 by Sensei

[John Cuthber]

14 hours ago, DanielBoyd said:

That is the assumption I am challenging with this article.

I'm sure I am not the only one looking forward to the evidence for this (along with some evidence for your other claims).

Incidentally, it's an acceptable shorthand within the scientific community to refer to " a gene for" when you actually mean (some set of genes which interact...."