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Author | Topic: Y.E.C. Model: Was there rapid evolution and speciation post flood? | |||||||||||||||||||||||||||||||||||||||||||
Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
bluegenes writes: This as a massive increase in functional information since Adam and Eve. Just from what we know about tissue transplantation we already knew that there was a wide range of function in these alleles. The reason that finding donors is difficult is because the binding specificities of the HLA proteins has to match or be very close, and there are hundreds of alleles out there with different binding specificities. If, as Faith hypothesizes, there are only two alleles per HLA protein then it should be quite easy to find perfect matches, but that just doesn't happen with any regularity.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Percy writes: If only 3 class I genes are involved, and only 3 (sometimes 4) class II genes, then now I'm confused why Taq gave me a diagram and an Excel list of all the MHC genes. The MHC complex includes antigen presenting proteins and other proteins. It isn't exclusive to antigen presenting proteins. It's a bit like getting an inventory of everything in the Louvre. There are going to be paintings and statues on the list, but there are also going to be mops and buckets on the list.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2
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Percy writes: Am I right about the point we're trying to make to Faith? If so, has the data I'm looking for been presented? If so, could someone point me to it? I presented a paper in post 270 that discusses many different alleles (i.e. much greater than 2) for HLA-A and HLA-B that have different function. Jar [edit: bluegenes] and I also discuss the paper in posts 271 and 277. What they did was chop up proteins from the dengue virus and determine which of these chopped up proteins, called peptides, bound to which allele for both HLA-A and HLA-B. What they found is that different peptides bound to different alleles. No two alleles bound the same peptides. HLA-A and HLA-B are antigen presenting proteins, so when they bind different viral peptides it indicates that they differ in function. Each gene has more than two functions spread out over many alleles which directly contradicts Faith's claims. Edited by Taq, : No reason given.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2
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Faith writes: It should be pretty clear by now that there isn't any. That is not an honest statement since you have already stated that your religious beliefs require you to reject the evidence that has already been presented.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Not Jar writes: I'm many things, but I'm not "a wide-mouthed cylindrical container made of glass or pottery." My apologies. The previous post has been edited to reflect my mistake.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Faith writes: First it would have to be shown that this binding does something beneficial to the immune system. The HLA-A and HLA-B proteins bind viral peptides and present them on the surface of the cell where they stimulate immune cells that fight off the infection. That is beneficial.
But also it's all about one disease, Dengue fever. What would it prove about different functions of different alleles when it's all about one disease? Why couldn't it demonstrate different functions with reference to one disease?
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Percy writes: Don't you mean that the peptides bound to the proteins produced by the alleles? That is what I was trying to communicate. I wanted to differentiate between viral proteins and HLA proteins just to make it clear.
The problem is that I can't understand the paper well enough to see how it supports this point. It is a bit dense, I will admit. The gist of it is that they looked at the sequence of each HLA allele and used a computer algorithm to predict which peptides it would bind. They then took the top 1% of predicted viral peptides and added them to the HLA proteins to see how well they bound in real life. From that data you can conclude that different alleles of each HLA gene bind a wide array of peptides, but not others. Also, HLA proteins from different alleles bind different viral peptides.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2
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Percy writes: So computer simulation predicted which peptides would bind to which alleles (which really means binding to the proteins produced by each allele), but what does the "top 1% of predicted viral peptides" mean? Does that mean predicted with the highest confidence? And then they ran laboratory experiments to see how well the predictions turned out? I believe top 1% refers to the binding avidity which is where you see reference to >500 nM. Avidity refers to the ability to grab something and not let go. Two of the main characteristics for protein binding are specificity and avidity. As you correctly state, then then made those small peptides to see how accurate their predictions were.
Percy writes: Do you mean that some alleles bind to a wide array of peptides, and some don't? It was poorly worded on my side. What I am saying is that there are many peptides the HLA proteins will bind, and a wide array that they won't bind. Each HLA allele has a different list of peptides that they will bind, also known as a difference in specificity.
The next thing that Faith wants to know is how the connection is made between binding to different peptides and improving the performance of the immune system. Although the HLA proteins were only tested against dengue virus, the same pattern carries over to other pathogens. Different alleles will bind differently to certain pathogens, changing the defenses you have against those pathogens. I believe bluegenes listed some of those examples in previous posts.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Percy writes: I think Faith would object that you've got computer simulations and laboratory experiments that show alleles binding to different peptides, but that that's not evidence that they have different functions. A change in binding specificity is a change in function by every definition used in biology.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Faith writes: Faith is looking at outcome to determine change in function. If allele A binds to peptide X and dengue fever goes away, and if allele B binds to peptide Y and dengue fever goes away, that isn't a difference in function. Function is not a synonym for outcome. What these alleles demonstrate is that different functions can produce the same outcome. More to your point, bluegenes already referenced how different alleles do result in different outcomes. For example, different alleles are more effective at fighting off malaria or HIV.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Percy writes: Faith will have to confirm, but I think for her the outcome she can observe is what is key. Different chemical pathways to the same outcome is a difference without a distinction for her. The problem is that Faith's views are not relevant to how biology actually works. You can't start with two HLA-B alleles and produce all of the observed functional diversity of HLA-B proteins. If you do start with two HLA-B alleles, then you need lots of mutations to produce the functional diversity for the HLA-B gene.
Let me recount the rough details on this one. The HLA-B53 allele fights malaria, and another HLA-B allele fights another form of malaria, and other HLA-B alleles are effective against HIV. Other HLA-B alleles fight other diseases, such as dengue fever. So the HLA-B gene is an example of different alleles producing different outcomes. That meshes with what I have read on the subject. It really isn't that surprising given how different HLA alleles bind to different peptides derived from human pathogens. This will almost necessarily result in different outcomes for different pathogens. If there are situations where there is strong natural selection, such as in the case of pathogens linked to high mortality rates (e.g. HIV, malaria), we can see selection for specific HLA alleles in those populations.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
NoNukes writes: The real question for blood type is why three is sufficient. Four would be required. For human beta-hemoglobin there are at least 3 alleles with different functions. There is HbA, HbS, and HbC. The A allele is the most common. The S allele is the sickle cell trait which confers resistance to malaria while also causing problems with your red blood cells. The C allele also confers resistance to malaria but it does not have the same deleterious side effects compared to the S allele. This is yet another example of a human gene with more than 2 alleles.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Percy writes: What she has a problem with is more than 2 alleles where the additional alleles do anything different than the original alleles. That was the context I was using. If Faith defines alleles by function then there are more than two alleles for that gene.
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Percy writes: What this table tells us is that we know very little about which HLA-B alleles protect against which pathogens. You can add influenza to the list: "To study whether individual HLA class I alleles are used preferentially or equally in human virus-specific CTL responses, the contribution of individual HLA-A and -B alleles to the human influenza virus-specific CTL response was investigated. To this end, PBMC were obtained from three groups of HLA-A and -B identical blood donors and stimulated with influenza virus. In the virus-specific CD8(+) T cell population, the proportion of IFN-gamma- and TNF-alpha-producing cells, restricted by individual HLA-A and -B alleles, was determined using virus-infected C1R cells expressing a single HLA-A or -B allele for restimulation of these cells. In HLA-B*2705- and HLA-B*3501-positive individuals, these alleles were preferentially used in the influenza A virus-specific CTL response, while the contribution of HLA-B*0801 and HLA-A*0101 was minor in these donors."Preferential HLA usage in the influenza virus-specific CTL response - PubMed
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Taq Member Posts: 10073 Joined: Member Rating: 5.2 |
Faith writes: When someone says that "for all we know such and such an allele might have protected our ancestors from sucn and such a disease" we're deep in evo territory. There are many alleles involved in the immune system some of whose function or phenotypic effect are known, but as Percy's charts point out a lot of them are redundant, doing the same thing. And a lot are unknown. I think this implies that the statement in the article back toward the beginning of the thread that all these alleles are a good thing because they imply the many differences in function needed to protect against the many differences in diseases, isn't really justified. They aren't redundant. There are many, many alleles that differ in function for the HLA genes. It is just a fact. The idea that you can't make any changes to the human genome without causing harm, or no phenotypic changes at all, is also untenable. If we compare the human genome to any other primate species we can immediately see that the possible beneficial changes to the human genome are numerous because those beneficial changes are found in other primate species.
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