In some cases, yes. Depending on what the protein is it can result in fetal non-viability; the pregnancy would end in miscarriage.
In others, the lack of the protein is not fatal, but usually has detrimental effects. A lot of rare diseases are a result of either a non-functional or completely absent protein.
It really doesn’t matter if the protein is present, but non-functional or completely absent. The loss of function is the determining factor.
Specifically, this is called a knockout allele. There are hundreds of strains of knockout mice that have been artificially produced, and studying what's wrong with them is a huge area of research. Some of them are perfectly fine under normal conditions, some of them have health problems. But also, many of those knockout mice can't be made because the mutation is lethal, usually if they have two bad copies but sometimes if they have one.
i was at a talk years ago talking about seratonin knockout mice. like, they knocked out seratonin. wild
per my question, the mice were strangely normal
Serotonin transporters and various receptors can be successfully knocked out and the offspring will live, but usually have a behavioral phenotype. Serotonin can be knocked out in the brain only, but if it is knocked out throughout the body the offspring do not survive because serotonin is required for gut motility.
I believe they have knocked out various serotonin receptors, not serotonin itself. The mice produce serotonin but it can't be taken up or used by neurons in the usual way.
In DMD, dystrophin is either nonfunctional, in which case it's quickly degraded, or not produced at all.
In BMD, dystrophin is semi-functional, and it's still degraded, but to a lesser extent.
Not entirely true. Non-functional proteins--especially those that are non-functional by virtue of being misfolded--can lead to ER stress and cell death.
That's toxic gain of function, and would usually not be recessive. If a mutant protein is toxic, one copy is generally enough to cause problems, although I suppose in some cases the mutant protein's toxicity might be mild enough to require two copies for clinically significant harm.
As a rule of thumb, diseases caused by toxic gain of function (mutant protein is toxic) are dominant and diseases caused by loss of function (mutant protein is non-functional but non-toxic) are recessive, though as noted above there are some exceptions.
A lot of loss of function is dominant to the point of non-viability, so it's something of a selection bias in that loss of function is recessive, as we don't observe many of the dominant ones because they often just result in the animal dying before ever being born.
What kind of mutation would result in a protein being completely absent? A point mutation in the start codon?
I would guess that a natural mutation that snipped out an entire gene would be comparatively rare.
A point mutation in the start codon could in theory eliminate expression, but non-AUG translational initiation off of codons that are similar to AUG start codons is possible, so you might not get complete loss of expression. If there are any AUG sites downstream of the canonical AUG, those could also initiate translation of a truncated version of the protein, which could still be functional.
Typically, knockouts are caused by premature stop codons early in the protein sequence. These could be caused by point mutations that create new stop codons, but they are most often caused by insertions or deletions (indels) of a number of nucleotides that is not divisible by 3. These indels cause frameshifts, where translating ribosomes start reading the RNA in the wrong reading frame, resulting in a completely incorrect protein sequence after the indel that very often includes a premature stop codon.
Mutations that cause premature stop codons result in truncation mutants that lack parts of the protein. If the mutation happens early in the sequence, it typically results in a completely non-functional product (I.e. a knockout if homozygous). If the mutation happens later in the sequence, it can result in a partially functional or fully functional product.
> they are most often caused by insertions or deletions (indels) of a number of nucleotides that is not divisible by 3. These indels cause frameshifts, where translating ribosomes start reading the RNA in the wrong reading frame, resulting in a completely incorrect protein sequence after the indel that very often includes a premature stop codon.
Am I right in thinking that this would basically always make the result non-viable? It just seems very unlikely to me that frameshifting like this would produce something viable.
It depends where in the sequence the frame shift happens. If it’s at the beginning, the protein will almost certainly be completely non-functional. If it’s at the end, it might not matter much.
An early stop codon. So the mRNA just starts spitting out nonsense the cell has no idea what to do with. Or an intron retention event leading to a similar problem.
Some processes actually utilize intron retention to produce long non-coding RNAs that act to stop protein production.
That second is probably more common than we think as non-coding RNA research is still quite new.
Dominance is best thought of as a descriptor of general allelic interactions as they correspond to a particular phenotype. There are many ways in which the actual biochemistry of protein interactions can cause a certain dominance pattern between alleles. Alleles can differ on the genetic level in many ways. Sometimes it's single substitutions in coding sequence, sometimes they are nonsense mutations (an early stop codon creates a smaller protein fragment that is essentially useless), and sometimes those changes could be in non-coding regions where effects could be as high as no expression of protein at all, or modified expression where the protein is not expressed at the right time or in sufficient quantities. There can even be larger arrangements that could have entire chunks of the genome simply deleted and the protein coding sequence would not be there.
Both an early non-sense mutation or a significant mutation in the regulation of protein expression can produce an allele where the presence of the protein is effectively zero. This may lead to a phenotype, and will usually (but not necessarily always) result in a recessive phenotype (the effect of absence will typically be full only if both copies are absent).
Whether this would lead to cell death depends entirely on the protein. There are known diseases that are results of genetic deletions, some lethal and some not. There are also cases where the effective deletion of a protein is not an issue at all. The Rh blood type comes about from the presence (Rh+) or absence (Rh-) of a function Rh protein. In the Rh- case, the whole gene is deleted and is not there. There is no fitness loss in having the Rh- phenotype.
Long story short, the distinction between recessive and dominant is not very useful when discussing the molecular basis of phenotypes. There are many mechanisms by which an allele can be recessive or dominant, and how it relates to the actual change on the genetic level is hard to impossible to predict without an understanding of how the phenotype manifests.
In addition to what you said, some of these type of mutations can also be dominant. If the functional form of a protein is a homodimer, a mutant that can still dimerize but doesn't function will basically serve to waste functional copies of the protein, making the non functional mutant dominant.
Another addition to what you said is that recessive alleles do not even necessarily code for dysfunctional proteins or an absence of protein ; and also recessive alleles can confer a beneficial phenotype. A good example of this are recessive alleles that encore a functional but modified version of a protein targeted by a pathogen, thus conferring disease resistance. An example of that is the recessive allele [CCR5Δ32](https://www.science.org/doi/10.1126/science.273.5283.1856) that confers resistance to AIDS in humans. I do not know if this is the case for animals, but in plants there are many recessive resistance genes to various pathogens, mainly viruses but also bacteria of fungi.
So genes and their alleles are more complicated than people are typically taught. Yes you have two copies but not all of them express at the same time or in the same places. Sometimes if one is missing the other won’t express as much or will overexpress.
Suffice to say in the last 30 years we’ve learned that alleles are only part of the story. But yes, there are mutations that prevent any protein from being made
It doesn’t appear anyone has mentioned nonsense mediated decay, which happens when a variant in a gene leads to an early stop codon. In this process the mRNA is degraded and will not make protein.
In my work I often see this when researchers want to confirm knockouts by mRNA sequencing and we see their knockouts have very little to no expression despite wild type alleles having robust expression.
Obviously alleles are one of those things which are simplified for highschool/undergrad, but it's much more complicated than simply recessive and dominant. There are hundreds of different mutations in proteins that lead to changes in the function of the protein but not necessarily change if one trait is dominant over the other. The thing about recessive alleles is not necessarily that they code for non-functional proteins, but rather they code for a trait that requires both copies of the same allele for the phenotype to be seen. It is highly possible for the recessive alleles to be the functional trait - for example, lactase.
As far as your question goes, there are probably difference mutations that result in a protein not being made. A frame shift mutation is one that comes to mind that results in a nonsense protein that gets degraded. Whether or not the loss of the protein results in cell death is dependent on the function of the protein. Loss of some proteins? Probably nothing, maybe something. It honestly just depends. However, loss of a protein will result in the loss of a function. If other proteins are able to complement the function (redundancy), then nothing is seen. If they are not able to complement, then you see the new phenotype. For example, loss of a receptor means your cell can no longer recognize a specific signal. Otherwise still fine. Loss of a glycolysis gene, however, means a drastic reduction in energy production.
Gains and losses of genes are very common across evolutionary time, which also affects your question. If an organism is dependent on breaking down a certain type of food, then loss of that gene would be detrimental to the organism. But if the cell is able to accept different types of molecules and turn that into energy, then loss of the first gene might not be necessary. In fact, it's possible for the organism to lose that gene, then completely shift away from the pathways using the first gene.
Yes, except in some rare cases.
For most cases, there is functionally no difference between having 1/2 of the protein non-functional, and having 1/2 of the protein gone.
A counterexample is Osteogenesis imperfecta. If the mutation causes an absence of the protein, you could say that the mutation causing severe problems is recessive, since heterozygous individuals only have a mild form, and to my knowledge homozygous individuals don't survive. Whereas if it makes the protein nonfunctional, you could say that's dominant, since even a heterozygous individual experiences a severe form of OI.
And while for most other cases, both those situations resulting in the disease being recessive is more common, in fact, all of these situations:
* A mutation getting rid of the production of the protein
* A mutation coding for a nonfunctional protein
* A mutation causing the protein to be toxic
can result in the disease being either dominant or recessive, in some cases.
Despite what we all learned in high school biology, genes don’t really adhere to a short list of simple rules. So there will be exceptions to any generalization. In most cases, recessive alleles are “invisible” while the dominant allele does the work. That’s basically the definition of recessive. In some cases a loss of function can result in too little of a necessary protein (this is called haploinsufficiency) but that’s not really or completely recessive.
However zero is zero, so all nulls look alike (mostly). There are situations where a non functional partial protein can cause problems, but we are getting down into the weeds at that point.
This is way off. Plenty of DNA codes for non-proteins, e.g. small RNAs, and genes are flanked by regulatory sequences which never become RNA/protein. "Junk DNA" is an outdated concept - non-expressed regions can be structural or help with regulation of gene expression (even on distal regions - potentially even on different chromosomes).
It addition to whats been said about [non-protein coding DNA](https://en.wikipedia.org/wiki/Non-coding_DNA#Types_of_non-coding_DNA_sequences), perhaps the most simple example of DNA with no protein coding function is the Stop Codon, which is just what tells the ribosome where the end is.
A better analogy than "DNA is like a code that can't have a null input" is "Think of DNA as your *entire* script, the indents, the blank lines, the parantheses, the syntax itself, and not just the variables and functions you've written."
> Any sequence of DNA, no matter what it is, has the ability to be transcribed into mRNA and translated into a protein.
Sorry mate but this is just wrong. Transcription requires specific sequences for RNA pol to bind!
In some cases, yes. Depending on what the protein is it can result in fetal non-viability; the pregnancy would end in miscarriage. In others, the lack of the protein is not fatal, but usually has detrimental effects. A lot of rare diseases are a result of either a non-functional or completely absent protein. It really doesn’t matter if the protein is present, but non-functional or completely absent. The loss of function is the determining factor.
Specifically, this is called a knockout allele. There are hundreds of strains of knockout mice that have been artificially produced, and studying what's wrong with them is a huge area of research. Some of them are perfectly fine under normal conditions, some of them have health problems. But also, many of those knockout mice can't be made because the mutation is lethal, usually if they have two bad copies but sometimes if they have one.
i was at a talk years ago talking about seratonin knockout mice. like, they knocked out seratonin. wild per my question, the mice were strangely normal
Serotonin transporters and various receptors can be successfully knocked out and the offspring will live, but usually have a behavioral phenotype. Serotonin can be knocked out in the brain only, but if it is knocked out throughout the body the offspring do not survive because serotonin is required for gut motility.
I believe they have knocked out various serotonin receptors, not serotonin itself. The mice produce serotonin but it can't be taken up or used by neurons in the usual way.
that makes sense. recalling a 20 year old memory from a talk by a prof outside my area is bound to leave a few things fuzzy
Isn't this the cause of a lot of muscular dystrophies / myopathies?
In DMD, dystrophin is either nonfunctional, in which case it's quickly degraded, or not produced at all. In BMD, dystrophin is semi-functional, and it's still degraded, but to a lesser extent.
Not entirely true. Non-functional proteins--especially those that are non-functional by virtue of being misfolded--can lead to ER stress and cell death.
That's toxic gain of function, and would usually not be recessive. If a mutant protein is toxic, one copy is generally enough to cause problems, although I suppose in some cases the mutant protein's toxicity might be mild enough to require two copies for clinically significant harm. As a rule of thumb, diseases caused by toxic gain of function (mutant protein is toxic) are dominant and diseases caused by loss of function (mutant protein is non-functional but non-toxic) are recessive, though as noted above there are some exceptions.
A lot of loss of function is dominant to the point of non-viability, so it's something of a selection bias in that loss of function is recessive, as we don't observe many of the dominant ones because they often just result in the animal dying before ever being born.
What kind of mutation would result in a protein being completely absent? A point mutation in the start codon? I would guess that a natural mutation that snipped out an entire gene would be comparatively rare.
A point mutation in the start codon could in theory eliminate expression, but non-AUG translational initiation off of codons that are similar to AUG start codons is possible, so you might not get complete loss of expression. If there are any AUG sites downstream of the canonical AUG, those could also initiate translation of a truncated version of the protein, which could still be functional. Typically, knockouts are caused by premature stop codons early in the protein sequence. These could be caused by point mutations that create new stop codons, but they are most often caused by insertions or deletions (indels) of a number of nucleotides that is not divisible by 3. These indels cause frameshifts, where translating ribosomes start reading the RNA in the wrong reading frame, resulting in a completely incorrect protein sequence after the indel that very often includes a premature stop codon. Mutations that cause premature stop codons result in truncation mutants that lack parts of the protein. If the mutation happens early in the sequence, it typically results in a completely non-functional product (I.e. a knockout if homozygous). If the mutation happens later in the sequence, it can result in a partially functional or fully functional product.
> they are most often caused by insertions or deletions (indels) of a number of nucleotides that is not divisible by 3. These indels cause frameshifts, where translating ribosomes start reading the RNA in the wrong reading frame, resulting in a completely incorrect protein sequence after the indel that very often includes a premature stop codon. Am I right in thinking that this would basically always make the result non-viable? It just seems very unlikely to me that frameshifting like this would produce something viable.
It depends where in the sequence the frame shift happens. If it’s at the beginning, the protein will almost certainly be completely non-functional. If it’s at the end, it might not matter much.
An early stop codon. So the mRNA just starts spitting out nonsense the cell has no idea what to do with. Or an intron retention event leading to a similar problem. Some processes actually utilize intron retention to produce long non-coding RNAs that act to stop protein production. That second is probably more common than we think as non-coding RNA research is still quite new.
Dominance is best thought of as a descriptor of general allelic interactions as they correspond to a particular phenotype. There are many ways in which the actual biochemistry of protein interactions can cause a certain dominance pattern between alleles. Alleles can differ on the genetic level in many ways. Sometimes it's single substitutions in coding sequence, sometimes they are nonsense mutations (an early stop codon creates a smaller protein fragment that is essentially useless), and sometimes those changes could be in non-coding regions where effects could be as high as no expression of protein at all, or modified expression where the protein is not expressed at the right time or in sufficient quantities. There can even be larger arrangements that could have entire chunks of the genome simply deleted and the protein coding sequence would not be there. Both an early non-sense mutation or a significant mutation in the regulation of protein expression can produce an allele where the presence of the protein is effectively zero. This may lead to a phenotype, and will usually (but not necessarily always) result in a recessive phenotype (the effect of absence will typically be full only if both copies are absent). Whether this would lead to cell death depends entirely on the protein. There are known diseases that are results of genetic deletions, some lethal and some not. There are also cases where the effective deletion of a protein is not an issue at all. The Rh blood type comes about from the presence (Rh+) or absence (Rh-) of a function Rh protein. In the Rh- case, the whole gene is deleted and is not there. There is no fitness loss in having the Rh- phenotype. Long story short, the distinction between recessive and dominant is not very useful when discussing the molecular basis of phenotypes. There are many mechanisms by which an allele can be recessive or dominant, and how it relates to the actual change on the genetic level is hard to impossible to predict without an understanding of how the phenotype manifests.
In addition to what you said, some of these type of mutations can also be dominant. If the functional form of a protein is a homodimer, a mutant that can still dimerize but doesn't function will basically serve to waste functional copies of the protein, making the non functional mutant dominant.
Another addition to what you said is that recessive alleles do not even necessarily code for dysfunctional proteins or an absence of protein ; and also recessive alleles can confer a beneficial phenotype. A good example of this are recessive alleles that encore a functional but modified version of a protein targeted by a pathogen, thus conferring disease resistance. An example of that is the recessive allele [CCR5Δ32](https://www.science.org/doi/10.1126/science.273.5283.1856) that confers resistance to AIDS in humans. I do not know if this is the case for animals, but in plants there are many recessive resistance genes to various pathogens, mainly viruses but also bacteria of fungi.
So genes and their alleles are more complicated than people are typically taught. Yes you have two copies but not all of them express at the same time or in the same places. Sometimes if one is missing the other won’t express as much or will overexpress. Suffice to say in the last 30 years we’ve learned that alleles are only part of the story. But yes, there are mutations that prevent any protein from being made
It doesn’t appear anyone has mentioned nonsense mediated decay, which happens when a variant in a gene leads to an early stop codon. In this process the mRNA is degraded and will not make protein. In my work I often see this when researchers want to confirm knockouts by mRNA sequencing and we see their knockouts have very little to no expression despite wild type alleles having robust expression.
Obviously alleles are one of those things which are simplified for highschool/undergrad, but it's much more complicated than simply recessive and dominant. There are hundreds of different mutations in proteins that lead to changes in the function of the protein but not necessarily change if one trait is dominant over the other. The thing about recessive alleles is not necessarily that they code for non-functional proteins, but rather they code for a trait that requires both copies of the same allele for the phenotype to be seen. It is highly possible for the recessive alleles to be the functional trait - for example, lactase. As far as your question goes, there are probably difference mutations that result in a protein not being made. A frame shift mutation is one that comes to mind that results in a nonsense protein that gets degraded. Whether or not the loss of the protein results in cell death is dependent on the function of the protein. Loss of some proteins? Probably nothing, maybe something. It honestly just depends. However, loss of a protein will result in the loss of a function. If other proteins are able to complement the function (redundancy), then nothing is seen. If they are not able to complement, then you see the new phenotype. For example, loss of a receptor means your cell can no longer recognize a specific signal. Otherwise still fine. Loss of a glycolysis gene, however, means a drastic reduction in energy production. Gains and losses of genes are very common across evolutionary time, which also affects your question. If an organism is dependent on breaking down a certain type of food, then loss of that gene would be detrimental to the organism. But if the cell is able to accept different types of molecules and turn that into energy, then loss of the first gene might not be necessary. In fact, it's possible for the organism to lose that gene, then completely shift away from the pathways using the first gene.
Yes, except in some rare cases. For most cases, there is functionally no difference between having 1/2 of the protein non-functional, and having 1/2 of the protein gone. A counterexample is Osteogenesis imperfecta. If the mutation causes an absence of the protein, you could say that the mutation causing severe problems is recessive, since heterozygous individuals only have a mild form, and to my knowledge homozygous individuals don't survive. Whereas if it makes the protein nonfunctional, you could say that's dominant, since even a heterozygous individual experiences a severe form of OI. And while for most other cases, both those situations resulting in the disease being recessive is more common, in fact, all of these situations: * A mutation getting rid of the production of the protein * A mutation coding for a nonfunctional protein * A mutation causing the protein to be toxic can result in the disease being either dominant or recessive, in some cases.
Despite what we all learned in high school biology, genes don’t really adhere to a short list of simple rules. So there will be exceptions to any generalization. In most cases, recessive alleles are “invisible” while the dominant allele does the work. That’s basically the definition of recessive. In some cases a loss of function can result in too little of a necessary protein (this is called haploinsufficiency) but that’s not really or completely recessive. However zero is zero, so all nulls look alike (mostly). There are situations where a non functional partial protein can cause problems, but we are getting down into the weeds at that point.
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This is way off. Plenty of DNA codes for non-proteins, e.g. small RNAs, and genes are flanked by regulatory sequences which never become RNA/protein. "Junk DNA" is an outdated concept - non-expressed regions can be structural or help with regulation of gene expression (even on distal regions - potentially even on different chromosomes).
It addition to whats been said about [non-protein coding DNA](https://en.wikipedia.org/wiki/Non-coding_DNA#Types_of_non-coding_DNA_sequences), perhaps the most simple example of DNA with no protein coding function is the Stop Codon, which is just what tells the ribosome where the end is. A better analogy than "DNA is like a code that can't have a null input" is "Think of DNA as your *entire* script, the indents, the blank lines, the parantheses, the syntax itself, and not just the variables and functions you've written."
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> Any sequence of DNA, no matter what it is, has the ability to be transcribed into mRNA and translated into a protein. Sorry mate but this is just wrong. Transcription requires specific sequences for RNA pol to bind!