PILOT SPIN
Spin Zone => Spin Zone => Topic started by: Rush on December 04, 2022, 09:43:05 AM
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@Steingar or anybody who knows the answer:
Given that genes consist of nucleobases A, C, T, G, which are made up of elements which are made up of molecules and atoms, do spontaneous mutations occur because atoms are exchanged/replaced on a regular basis, opening a chance for mistakes? Or do they “break” for unknown random reasons? (Excluding known causes such as radiation.)
Asking for a friend.
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That's a non-trivial question. Your answer is in chapter 5 of Molecular Biology of the Cell, among other texts. The 4th edition is online here:
https://www.ncbi.nlm.nih.gov/books/NBK21054/ (https://www.ncbi.nlm.nih.gov/books/NBK21054/)
But the NIH doesn't allow its contents to be browsed - only searched. Fortunately I have a Kindle copy of the 6th edition (they release new editions about once every ten years, it is considered among the best texts on the subject) and here is what the start of Chapter 5 says:
Chapter 5: DNA Replication, Repair, and Recombination
The ability of cells to maintain a high degree of order in a chaotic universe depends upon the accurate duplication of vast quantities of genetic information carried in chemical form as DNA. This process, called DNA replication, must occur before a cell can produce two genetically identical daughter cells. Maintaining order also requires the continued surveillance and repair of this genetic information, because DNA inside cells is repeatedly damaged by chemicals and radiation from the environment, as well as by thermal accidents and reactive molecules generated inside the cell. In this chapter, we describe the protein machines that replicate and repair the cell’s DNA. These machines catalyze some of the most rapid and accurate processes that take place within cells, and their mechanisms illustrate the elegance and efficiency of cell chemistry.
While the short-term survival of a cell can depend on preventing changes in its DNA, the long-term survival of a species requires that DNA sequences be changeable over many generations to permit evolutionary adaptation to changing circumstances. We shall see that despite the great efforts that cells make to protect their DNA, occasional changes in DNA sequences do occur. Over time, these changes provide the genetic variation upon which selection pressures act during the evolution of organisms.
We begin this chapter with a brief discussion of the changes that occur in DNA as it is passed down from generation to generation. Next, we discuss the cell mechanisms—DNA replication and DNA repair—that are responsible for minimizing these changes. Finally, we consider some of the most intriguing pathways that alter DNA sequences—in particular, those of DNA recombination including the movement within chromosomes of special DNA sequences called transposable elements.
THE MAINTENANCE OF DNA SEQUENCES
Although, as just pointed out, occasional genetic changes enhance the long-term survival of a species through evolution, the survival of the individual demands a high degree of genetic stability. Only rarely do the cell’s DNA-maintenance processes fail, resulting in permanent change in the DNA. Such a change is called a mutation, and it can destroy an organism if it occurs in a vital position in the DNA sequence.
Mutation Rates Are Extremely Low
The mutation rate, the rate at which changes occur in DNA sequences, can be determined directly from experiments carried out with a bacterium such as Escherichia coli—a resident of our intestinal tract and a commonly used laboratory organism (see Figure 1–24). Under laboratory conditions, E. coli divides about once every 30 minutes, and a single cell can generate a very large population— several billion—in less than a day. In such a population, it is possible to detect the small fraction of bacteria that have suffered a damaging mutation in a particular gene, if that gene is not required for the bacterium’s survival. For example, the mutation rate of a gene specifically required for cells to use the sugar lactose as an energy source can be determined by growing the cells in the presence of a different sugar, such as glucose, and testing them subsequently to see how many have lost the ability to survive on a lactose diet. The fraction of damaged genes underestimates the actual mutation rate because many mutations are silent (for example, those that change a codon but not the amino acid it specifies, or those that change an amino acid without affecting the activity of the protein coded for by the gene). After correcting for these silent mutations, one finds that a single gene that encodes an average-sized protein (~10^3 coding nucleotide pairs) accumulates a mutation (not necessarily one that would inactivate the protein) approximately once in about 10^6 bacterial cell generations. Stated differently, bacteria display a mutation rate of about three nucleotide changes per 10^10 nucleotides per cell generation.
Recently, it has become possible to measure the germ-line mutation rate directly in more complex, sexually reproducing organisms such as humans. In this case, the complete genomes from a family—parents and offspring—were directly sequenced, and a careful comparison revealed that approximately 70 new single-nucleotide mutations arose in the germ lines of each offspring. Normalized to the size of the human genome, the mutation rate is one nucleotide change per 10^8 nucleotides per human generation. This is a slight underestimate because some mutations will be lethal and will therefore be absent from progeny; however, because relatively little of the human genome carries critical information, this consideration has only a small effect on the true mutation rate. It is estimated that approximately 100 cell divisions occur in the germ line from the time of conception to the time of production of the eggs and sperm that go on to make the next generation. Thus, the human mutation rate, expressed in terms of cell divisions (instead of human generations), is approximately 1 mutation/10^10 nucleotides/cell division.
Although E. coli and humans differ greatly in their modes of reproduction and in their generation times, when the mutation rates of each are normalized to a single round of DNA replication, they are both extremely low and within a factor of three of each other. We shall see later in the chapter that the basic mechanisms that ensure these low rates of mutation have been conserved since the very early history of cells on Earth.
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Wow, Jim, thanks! That answers my question and then some!
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Wow, Jim, thanks! That answers my question and then some!
You're welcome. Though your question cost me $227.29. You see after I quoted the 6th edition Kindle text I decided to check my purchase date on Amazon. It informed me a newer 7th edition had been published this summer. Went to the publisher's web site and discovered it was cheaper to buy directly from them. Instead of the Kindle edition I bought the hard cover version. Even though the 6th edition Kindle version is very good, I yearned for a hard copy. The new version gave me a reason to buy a tome that will help exercise my wrists and biceps. And I've never been able to finish reading the Kindle version - somewhat unsatisfying for reasons I can't explain.
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You're welcome. Though your question cost me $227.29. You see after I quoted the 6th edition Kindle text I decided to check my purchase date on Amazon. It informed me a newer 7th edition had been published this summer. Went to the publisher's web site and discovered it was cheaper to buy directly from them. Instead of the Kindle edition I bought the hard cover version. Even though the 6th edition Kindle version is very good, I yearned for a hard copy. The new version gave me a reason to buy a tome that will help exercise my wrists and biceps. And I've never been able to finish reading the Kindle version - somewhat unsatisfying for reasons I can't explain.
Hahaha! Consider that your Christmas present to yourself!
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Mutations occur all the time for a number of reasons. Very few occur in germ cells, that is eggs and sperm. Those that do will occur in every cell of the offspring should the affected gamete achieve fertilization. The affected offspring will be heterozygous for the new allele, though could evince some phenotype should it be a gain of function or haploinsufficient.
Most mutations occur in somatic cells, that is those that aren't germ cells. They have a 5% chance to affect a protein sequence, since only about 5% of your genome encodes proteins. Should a mutation occur in a somatic cell it will be in all the descendants of that cell. If the mutation occurs in embryogenesis it can affect many cells, if it occurs later it affects fewer.
There are many processes that create mutations. Polymerases can put in the wrong base for a variety of reasons, things like adducts and tautomeric shifts can change base pairing, reactive oxygen species are made by the respiratory chain and can damage DNA, as can radiaction in the UV spectrum and higher.
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Mutations occur all the time for a number of reasons. Very few occur in germ cells, that is eggs and sperm. Those that do will occur in every cell of the offspring should the affected gamete achieve fertilization. The affected offspring will be heterozygous for the new allele, though could evince some phenotype should it be a gain of function or haploinsufficient.
I'm thinking serious mutations in in these could be responsible for most early miscarriages? (Defects incompatible with life.)
Most mutations occur in somatic cells, that is those that aren't germ cells. They have a 5% chance to affect a protein sequence, since only about 5% of your genome encodes proteins. Should a mutation occur in a somatic cell it will be in all the descendants of that cell. If the mutation occurs in embryogenesis it can affect many cells, if it occurs later it affects fewer.
There are many processes that create mutations. Polymerases can put in the wrong base for a variety of reasons, things like adducts and tautomeric shifts can change base pairing, reactive oxygen species are made by the respiratory chain and can damage DNA, as can radiaction in the UV spectrum and higher.
Ah, protein... the reason I'm asking is because of the CCND1 gene that encodes the cyclin D1 protein. i was wondering how that transcription happened, I guess we don't really know exactly why these spontaneous mutations occur. They are however, NOT heritable, not being in a germ cell?
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I'm thinking serious mutations in in these could be responsible for most early miscarriages? (Defects incompatible with life.)
Ah, protein... the reason I'm asking is because of the CCND1 gene that encodes the cyclin D1 protein. i was wondering how that transcription happened, I guess we don't really know exactly why these spontaneous mutations occur. They are however, NOT heritable, not being in a germ cell?
Most mutations in the ETS/CyclinD/Rb system are somatic and are found in numerous cancers. Inherited mutations in Rb cause a tumor in the eye of youngsters, if they recover they suffer other tumors later on.
The mutations in Rb remove the activity of the protein in one way or another. Cancer causing mutations in ETS/CyclinD/CDK4 are usually gain of function, and amplification or some other over expression event. Activity of the ETS/CyclinD/CDK4 is pro growth, and a good thing for tumor cells. Activity of Rb is antigrowth, it is a tumor suppressor, a brake on the cell cycle, something any self respecting tumor cell wants to go away.
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Most mutations in the ETS/CyclinD/Rb system are somatic and are found in numerous cancers. Inherited mutations in Rb cause a tumor in the eye of youngsters, if they recover they suffer other tumors later on.
The mutations in Rb remove the activity of the protein in one way or another. Cancer causing mutations in ETS/CyclinD/CDK4 are usually gain of function, and amplification or some other over expression event. Activity of the ETS/CyclinD/CDK4 is pro growth, and a good thing for tumor cells. Activity of Rb is antigrowth, it is a tumor suppressor, a brake on the cell cycle, something any self respecting tumor cell wants to go away.
Oh wow, so the Rb mutation can be inherited. How horrible to have a child have eye cancer. :'(
But in this case the somatic change in over expression of cyclinD results in mantle cell lymphoma and is acquired during life, spontaneously I gather. Therefore MCL is not inheritable.
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Oh wow, so the Rb mutation can be inherited. How horrible to have a child have eye cancer. :'(
But in this case the somatic change in over expression of cyclinD results in mantle cell lymphoma and is acquired during life, spontaneously I gather. Therefore MCL is not inheritable.
There is an extra wrinkle in Mantle Cell Lymphoma. The cells that go wrong are called B cells, they normally make antibodies. Antibodies are amazing, you make over a million different kinds. What's amazing is you only have about 25,000 genes and make perhaps 100,000 proteins. But a million antibodies.
The way B cells can do this is through a process called somatic recombination, that is moving bits of DNA around to make new molecules. It is a really amazing trick, but sometimes it goes wrong. Sometimes the wrong bits get spliced together, and you get what's called a translocation. In the case of MCL that translocation usually puts the Cyclin D1 gene right downstream of the Immunoglobulin Heavy Chain Enhancer, which causes a lot of gene expression in immune cells. Lots of a Cyclin is really bad.
Of course, these translations are in somatic cells, and can't be passed down to offspring.
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There is an extra wrinkle in Mantle Cell Lymphoma. The cells that go wrong are called B cells, they normally make antibodies. Antibodies are amazing, you make over a million different kinds. What's amazing is you only have about 25,000 genes and make perhaps 100,000 proteins. But a million antibodies.
A million is large, but rather understates the possible number a little:
"Scientists previously estimated that the human body can make at least a trillion unique antibodies. To explore the actual combination of antibodies people have developed, a team led by Drs. Bryan Briney and Dennis R. Burton at Scripps Research examined antibody-producing B cells isolated from blood samples of 10 people between the ages of 18 and 30. The research was supported in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Results were published online on January 21, 2019, in Nature.
Using large-scale genetic sequencing technologies and analytical software they developed, the researchers examined nearly 3 billion antibody heavy-chain sequences. Based on their findings, they estimated that the human antibody repertoire is much greater than previously thought—with the potential for the body to make a quintillion, or one million trillion, unique antibodies."
Source: Decoding the variety of human antibodies (https://www.nih.gov/news-events/nih-research-matters/decoding-variety-human-antibodies)
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A million is large, but rather understates the possible number a little:
"Scientists previously estimated that the human body can make at least a trillion unique antibodies. To explore the actual combination of antibodies people have developed, a team led by Drs. Bryan Briney and Dennis R. Burton at Scripps Research examined antibody-producing B cells isolated from blood samples of 10 people between the ages of 18 and 30. The research was supported in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Results were published online on January 21, 2019, in Nature.
Using large-scale genetic sequencing technologies and analytical software they developed, the researchers examined nearly 3 billion antibody heavy-chain sequences. Based on their findings, they estimated that the human antibody repertoire is much greater than previously thought—with the potential for the body to make a quintillion, or one million trillion, unique antibodies."
Source: Decoding the variety of human antibodies (https://www.nih.gov/news-events/nih-research-matters/decoding-variety-human-antibodies)
It is true that somatic recombination can make a staggering number of different antibodies. There are several different versions of each segment of the antibody, allowing for lots of different combinations. But added to that is a randomization as the bits are put together, an enzyme called terminal deoxynucleotydl transferase randomly adds nucleotides at the breakpoints pushing up the number of combinations even more.
What isn't limitless is the number of B and T cells, you can't have a quintillion of them. According to the internet you have 10 billion, so I'm off by 5 orders of magnitude. Oh well, immunology was never my strong suit.
Google "VDJ Recombination" if you want to kwon more, it's really cool.
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Hahaha! Consider that your Christmas present to yourself!
The present came today.
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Sixth Edition on an iPad Mini vs the Seventh Edition textbook.
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Sixth Edition on an iPad Mini vs the Seventh Edition textbook.
I try reading things like the ForeFlight manual or other FAA books through ForeFlight on my iPad mini and I just can’t get comfortable with that. Give me a paper book any day.
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I try reading things like the ForeFlight manual or other FAA books through ForeFlight on my iPad mini and I just can’t get comfortable with that. Give me a paper book any day.
I prefer paper books too, but ordering an ebook yields instant gratification. And searching an ebook for key words and phrases is something not possible with a paper book that has no index or a poorly made one.
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I prefer paper books too, but ordering an ebook yields instant gratification. And searching an ebook for key words and phrases is something not possible with a paper book that has no index or a poorly made one.
Have you ever been reading a paper book and looked around for the search button?
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Have you ever been reading a paper book and looked around for the search button?
Ha. I learned to create my own. In the 1990s I was on a kick to read every Tom Clancy novel at the time while I was commuting on a train to downtown Chicago. (Pre-cell phone and laptop era.)
One of the most challenging was “Cardinal of the Kremlin.” As you can imagine, all the Russian names start to look the same, so I started to write the name of each character inside the cover and noted the page number in which they first appeared. That way I could go back and refresh myself as to the circumstances when a character first appeared. I’ve been doing that with most complex novels ever since then.
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Ha. I learned to create my own. In the 1990s I was on a kick to read every Tom Clancy novel at the time while I was commuting on a train to downtown Chicago. (Pre-cell phone and laptop era.)
One of the most challenging was “Cardinal of the Kremlin.” As you can imagine, all the Russian names start to look the same, so I started to write the name of each character inside the cover and noted the page number in which they first appeared. That way I could go back and refresh myself as to the circumstances when a character first appeared. I’ve been doing that with most complex novels ever since then.
I did that once for a book series, “The Last Kingdom”. Everyone’s name started with “Aethel…” or “Ael…”
Aethelstan, Aethelwold, Aethelflaed, Aethelhelm, Aethelred
Aelswith, Aelflaed, Aelfwynn, Aelfweard, Aelfric
And then there was Cnut. No, I never misread that.
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And then there was Cnut. No, I never misread that.
Some of the younger women I now associate with (no not mine) love to use that word, you know, "C U next Tuesday", but they say the actual word. I respond, "language!". ;D