Somatic hypermutation is an amazing process which increases the diversity of the antibody response and can also lead to an increase in antibody affinity over time. As we noted in lecture, the human body has the potential to make 10 billion different antibodies from just a few gene regions and somatic hypermutation helps increase this diversity.
Somatic hypermutation is a process which essentially involves specific but semi-random mutation events which are focused only on a small region of the antibody genes. The small region just happens to be the binding site of antibodies for foreign antigens.
Mutations at large in the genome are often deleterious, yet somatic hypermutation and a process of selection leads to positive benefit for the host. Thus, from a design perspective we cannot say that all mutations or natural selection processes are neutral or bad or deleterious.
QUESTIONS
Give a brief explanation about how directed mutations work.
From a design perspective, why use a mutation process to increase antibody diversity and affinity?
What are some of the advantages involved in using a mutation system to increase immune function in this way?
DUE NOVEMBER 30
Directed mutations work by causing B Cells to mutate the antibodies they create, thus increasing the variation in antibodies in the body. Directed mutation typically works by introducing the B cells to an error prone DNA polymerase which will then create errors in the DNA and result in mutation. Another way to direct hypermutation is by incorporating an additional nucleotide into the DNA of a variable chain. This is done by using an enzyme called activation-induced deaminase (AID) to denature the DNA, then adding sgRNAs.
ReplyDeleteFrom a design perspective, mutation is used to increase antibody diversity because our bodies can not hold enough of each of the ten billion antibody combination, so it was designed to increase the diversity so that useful antibodies could be obatianed and unnecessary antibodies be neglected. This design also allows for multiple antibodies to be made for the same antigen which then allows the immune system to be more thorough.
Overall, directed somatic hypermutation is beneficial in increasing immune function because it creates a large library of antibodies without introducing all of the different variants of antibodies at once. Introducing all ten billion antibody combinations could be too much for an immune system and overload the immune system. This mutation system is also helpful because combinations that are similar to the first will be coded which allows for some variation of useful antibodies and little room for antibodies that will not bind to antigens.
Sources:
http://www.nature.com/nmeth/journal/vaop/ncurrent/full/nmeth.4038.html
https://www.ncbi.nlm.nih.gov/pubmed/15516361
https://www.ncbi.nlm.nih.gov/pubmed/17328676
I found it's interesting that you mentioned that mutation can create a large library of antibodies without introducing the different variants of antibodies at once. I was wondering if directed somatic hypermutation happens at birth or throughout our lifetime. Because there are enzymes in our body before birth that adds nucleotides to create diversity in B cells and T cell receptors. I know that there are a large amount of diversity already before birth, so I was wondering if mutation of such kind would add a larger amount or just a minute amount. Good work!
DeleteI would think that somatic hypermutation starts sometime after birth and through out our lives since it is classified as part of adaptive immunity. However, I'm not fully sure because antigens may be able to cross the placenta similar to how IgG crosses the placenta. Also, before birth, most of the baby's antibodies are from the mother and even after birth the infant continues to get antibodies from the mother through breast feeding, so it isn't clear if the baby's antibodies will begin mutating right away.
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ReplyDeleteMutations that increase the diversity and affinity of antibodies of the immune system are programmed processes, though random, are also directed by enzymes. The mutation process is first initiated by antigen binding to the antibody and triggers point mutation in the variable region of the immunoglobulin genes. This process is aided by the enzyme activation –induced deaminase (AID), which converts cytidine base to a uracil base. This in turn creates single nucleotide polymorphisms that once the mutated genes are transcribed and translated, the results are thousands of different immunoglobulin.
Mutation is often used by modern scientists to explain the theory of evolution whereby the generation of genetic differences among individuals is directly influenced by allelic changes. However from a design perspective, we can see that directed mutation processes, such as somatic hypermutation, are built-in features of God’s grand scheme of creation. Most people think of mutation as a random process. However in the case of somatic hypermutation, the system is very specific as to which antigens the diverse antibodies would attack. Mutation is necessarily designed in the immune system to provide diversification and affinity to myriads of antigens that an organism could encounter throughout its lifetime.
Mutation is a quick and “easy” way to generate an astronomical amount of different antibodies with myriad distinct functions that can combat various antigens. There are other methods that the immune system utilizes to generate diversity such as class switching recombination or gene conversion. These methods require various active enzymes, repair and regulation. Although mutation can be deleterious if not kept in check, most mutation processes occurred or initiated by small amount of enzymes, or directly influenced by environmental factors. Moreover, in the case of somatic hypermutation, the mutated genes are not passed on to the next generation, reducing the chances of defective proteins in the offspring.
When we think of mutations, we usually think about diseases, but this process is so incredibly designed! It is amazing to me that the immune cells can use mutation in such a regulated way and yet still protect the genome by not allowing any mutations to pass on to the next generations.
DeleteDirect mutation is the concept that cells can change their genes in response to an environmental stress. When foreign agents enter the system, peripheral B cells can mutate their genomic DNA to change their antigen affinity and isotype. This mechanism is regulated by activation induced deaminase (AID) which converts cytosine in the immunoglobulin loci into uracil. This creates a uracil:guanine mismatch. Since this is not normal, B cells are able to manipulate DNA repair function to be more or less efficient while still maintaining genomic integrity.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954419/
From a design perspective, a direct mutation process is used because it explains the specificity of the mutations which can not be random. Because it is so specific however, we can see that only God could design it that way. It does not fully explain, for example, how AID is preferentially targeted to the immunoglobulin loci.
http://www.annualreviews.org/doi/full/10.1146/annurev.biochem.76.061705.090740?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed&
A mutation system such as somatic hypermutation is advantageous because it mutations specifically occur on the immunoglobulin loci and only really requires AID. This is important because specificity increases sensitivity to ensure antigens are attacked. This process also keeps the integrity of the rest of the genome which decreases the chances of disfunction in the genome.
http://www.evolutionnews.org/2010/11/affinity_maturation_somatic_ce040331.html
all this research really shows how important the mutation system is. it helps create a wide variety of antibodies in order for our immune system to become well ready for pathogens in the external environment. It also shows that only God could have created this because of how specific it is.
DeleteI really like your concise answers Sherri, especially the answer to the last question. It is interesting that the process such as mutation that is regarded in a negative light can be advantageous in increasing the specificity of our immunity. And indeed it is not random that it was designed to switch up the genome to accomplish just that. Good work!
DeleteDirected mutation also known as directed mutagenesis is a hypothesis that proposes that living organisms can respond to environmental stresses by doing a direct mutation to one of their genes or areas of the genome. The hypothesis of directed mutation was first proposed in 1988 by a researcher name John Cairns. He studied Escherichia coli that lacked to metabolize lactose. He grew the bacteria in a environment that only had lactose as the source of energy. He found that the rate which the bacteria evolved the ability to metabolize lactose was many orders of magnitude higher the if mutations were random. http://jb.asm.org/content/186/15/4846
ReplyDeleteDirect mutation shows that these type of mutations can't be random. It is very specific just like how everything in creation is so specific in design that only a creator and designer who is God can only design it that way.
Somatic hyper mutation is advantageous and is a a critical process that helps create the essential antibody diversity to help develop our immune reponse to pathogens. Our genome encode a limited amount of antibody genes which is insufficient to generate antibodies against a wide scope of pathogens that we encounter on a daily basis. Somatic hypermutatation helps enable our immune system to expand the limited diversity encoded within our genomes to the bilions of antibody specificity require to fight against pathogens. https://www.anaptysbio.com/platform/somatic-hypermutation/
Somatic hypermutation is a process by which peripheral B cells modify their DNA without producing harmful mutations to the genome. This process is tightly coordinated and regulated through one specific protein called activation induced deaminase (AID). AID converts cytosine to uracil within the immunoglobulin loci, leading to a mutagenic deoxyuracil. In addition, B cells can also manipulate the DNA repair pathways to make sure that deoxyuracils are not repaired. AID is regulated at the transcription, translation, phosphorylation, ubiquitination, cellular localization, protein stability, and protein-protein interaction levels.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954419/
It seems like a strange thing to use a mutation process to increase diversity and affinity when talking about design because mutations are essentially malfunctions. However, the fact that the B cells can regulate mutation through the sheer amount of regulatory factors as well as possessing the ability to maintain genomic integrity shows more design than evolution to me. It is beyond amazing that a cell can control mutation and the fact that this process is not driven by “random” mutation is another great testament to our Creator.
Because our genomes encode a limited number of antibody genes, these mutations allow our immune system to expand antibody diversity. This is an essential process because of the multitude of different external pathogens out bodies are exposed to daily. Somatic Hypermutation allows the immune system to respond to a wide variety of foreign pathogens while needing the least amount of genomic material to do so. The original genome is kept safe because these mutations are so tightly regulated and the diversity of antibodies is increased exponentially. The immune system could not be as efficient without somatic hypermutation.
https://www.anaptysbio.com/platform/somatic-hypermutation/
I agree with you that the mutations really our a great testament to our Creator. It really is incredible that God chooses to help us fight off a myriad of antibodies through the ordered chaos of mutations, while at the same time showing his incredible design for our bodies. We serve a great and loving Creator!
Delete1. Directed mutations happen after the B cell has matured and has migrated to secondary lymphoid organs. As B cells continue to multiply after they come into contact with antigens the VDJ heavy and VJ light genes recombine. These mutated B cells produce membrane Ig with mutated binding sites that have higher affinity to specific antigens. If these altered antibodies do not bind to the antigen, they die. If the affinity is greater than the original, then a signal is sent to proliferate and mature into plasma cells. Because of this the affinity of the antibodies increases.
ReplyDelete2. From a design perspective, this directed mutation is a clear indicator of the complexities of creation that indicate there is a design. These mutations are random, but they aren’t started randomly. They begin and are designed to strengthen the antibody response to a specific antigen. The B cell doesn’t just mutate randomly in hopes that it might mutate in the right way to increase the affinity. The mutations are completely ordered and show that even in the haphazard system of mutation there is still great design and purpose. This is an evidence of the ordered and non chaotic nature of creation and is a small indication that everything doesn’t just happen by chance.
3. The advantages of using mutation to increase immune function are the great amount of diversity that stems from random recombination of genes. The amount of different combinations of genes that comes from mutation is incredibly great. The other advantage is that the B cell doesn’t need any additions from anything to make a variety of genes, it simply uses itself in the recombination to create the variety.
http://www.genetics.org/content/genetics/131/4/783.full.pdf
Deletehttp://www2.nau.edu/~fpm/immunology/Exams/antibodygenes.html
Melia, what an incredible portrayal of God's creativity in designing mutations that are random, and yet aren't started randomly in order to advance the protection of the immune system against antigens!
DeleteThanks for adding a more in depth description of directed mutation and how it actually amplifies immunity.
DeleteAlso appreciate both you and Annie acknowledge the randomness of the recombination but also how God designed it that way in creating the immune system.
Directed Mutagenesis is an evolutionary hypothesis on the genome, or genetic makeup of an organism, changing in response to either heritable conditions and semi-external stresses like heat, chemicals and radiation. Mutation from a Design perspective shows the intricate ability of the human body and its immune system to acclimate, thrive better and have better defense performance with an increase in antibody diversity for example. Mutation, especially beneficial somatic cell mutation, from a Design perspective edifies how our bodies were made complex (and amazing). This is in regards to slight mutations to survive better, and not the evolutionary theory that all of mankind is evolved versions of lower life forms and organisms like eukaryotes. Immune system capability enhancement is the main benefit to directed mutation. Increases antibody diversity means that our bodies would take in more and different types of antibodies in order to fight infections or disease. Deletion of certain base pairs lead to an immunity to the bubonic plague and small pox for example. Overall, mutations lead to better survival.
ReplyDeleteSources:
ReplyDeletehttps://etb-intelligent-design.blogspot.com/2012/03/random-mutations-and-intelligent-design.html
https://ghr.nlm.nih.gov/primer/mutationsanddisorders/genemutation
https://ghr.nlm.nih.gov/primer/mutationsanddisorders/possiblemutations
Directed mutation was first discovered by John Cairns in 1988 who found mutations in nutritionally deprived, non-dividing E. coli as an effect of selective pressure. The hypothesis developed from this discovery was that these mutations were “directed” by selective conditions. Since Cairn’s discovery, more has been observed about the nature of mutation processes. Mutations that increase the affinity and diversity of the antibodies on the cell begin with somatic hypermutation of the immunoglobulin genes. This hypermutation leads to a selection of higher-affinity B cell clones through the introduction of point mutations in the variable regions of the immunoglobulin genes by a set of complex proteins beginning with activation-induced cytidine deaminase (AID). The process is aided by several enzyme systems, but mutation is based heavily on the mutagenic activity of AID.
ReplyDeleteEvolutionists use directed mutation as a way to explain the theory of evolution by basing evolution as an outcome of genetic variants due to mutations activated by the environment. From a design perspective, however, directed mutation is not an accident, but was planned by God during creation as a way to increase the affinity and diversity of antibodies, as well as their exceptional specificity to certain antigens.
Mutation systems, such as somatic hypermutation, is advantageous in increasing immune function because it has the capacity to create an enormous amount of diverse antibodies that are each specific to a certain antigen in a short amount of time. Through the use of environmental factors and the activation of proteins by certain enzymes, mutation systems can increase the affinity, diversity, and specificity of antibodies on the cell that have a greater potential in protecting the individual and which are completely unique to that individual’s immune system.
http://www.annualreviews.org/doi/full/10.1146/annurev.immunol.26.021607.090236
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929355/
I appreciate how you compared the evolutionist view to creationism. I think it's very interesting how people looking at the same thing can jump to very different conclusions. Nonetheless, it is amazing how the Lord has designed these mutations to produce so much variety; and all to protect us!
DeleteDirected mutations occur at specific genomic locations in response to conditions related to selection. Hypermutation is simply an acceleration of these mutations. The mechanisms of somatic hypermutaions involve the deamination of cytosine to uracil in the DNA by Activation-Induced Deaminase. A mismatch in the DNA results and in order to maintain DNA integrity, the mutations are to be repaired. When mutations occur during the transcription/translation phases of the immunoglobulin variable region in B cells, results in the production of varying B cells.
ReplyDeleteFrom a design perspective I think there are many reasons why the Lord would create this process the way He did. I think one aspect could be related to the idea of “irreducible complexity.” Creation acts as general revelation for all humans, and this is just another (more detailed) example.
A major advantage in using mutations to increase immune function is evident in the numbers that result from it. It is also advantageous because no outside factors are really necessary. All the genetic information is present within the cell, and it has the ability (through recombinations) to produce a large variety of products.
Hi Samantha, I appreciate your focus on how directed mutations occur within our genomes. How awesome is it that the Lord provided us with a way to defend against virtually unlimited amounts of antigens? The fact that no outside factors are necessary for this process is just another evidence of His divine design.
DeleteIn 1988 John Cairns developed the directed mutation hypothesis which states that organisms can respond to environmental stresses through directing mutations to certain genes or areas of the genome. He found that E. coli lacking the ability to metabolize lactose would evolve this ability at a surprisingly high rate, leading to the question of whether or not the mutations were random. From this, he proposed that the mutations he observed had been directed at those genes involved in lactose consumption. Since then, his hypothesis has been validated and categorized in the following subgroups: targeted mutagenesis, insertional mutagenesis, transposon mutagenesis, and in vitro mutagenesis. Targeted mutagenesis is the deliberate change in the genetic structure directed at a specific site on the chromosome. Insertional mutagenesis is the mutagenesis of DNA by insertion of one or more bases. Transposon mutagenesis is a process that allows genes to be transferred to a host organism’s chromosome – interrupting, modifying the function of an extant gene on the chromosome and causing mutation. For informational purposes, a transposon is a piece of DNA that can hop around within a genome. In vitro mutagenesis is a collection of methods for creating mutations in specific and predetermined regions of DNA in the test tube – this can cause effects on behavior of the gene (Ghatak, L. Techniques and methods of biology (2011). eBook.)
ReplyDeleteFrom a creationist point of view, directed mutation is just another evidence of God’s divine design. He created our immune system to adapt. Through this process, we are then able to create an increase in diversity of antibodies to antigens – better preparing us for a greater number of immune threats. If our antibodies were only able to create a limited amount of variation, we would contract many more diseases/infections/viruses and consequently our death rates would be higher. However, God wrote a complex instructional manual into our genome, one which is flexible and easily adaptive. As such, the increased antibody diversity creates specific antibodies with high affinity to specific antigens – leading to a better-equipped defense system compared to if we could not produce directed mutations.
To sum up the advantages to such a non-random system of mutation, one could say that this process better fortifies our bodies against antigens. Directed mutation allows for greater variety in antibodies and as a result provides a better defense. An adaptive immune system means higher chances of immunity to higher numbers of antigens.