During an immune response, B cells get activated, which proliferate through cell division, and produce antibodies. These antibodies (Ab) bind to foreign particles (antigens, or Ag), and target them for attack. As the Bcells divide, an error-prone DNA polymerase is used to copy the regions for Ab, which leads to Ab production in daughter cells with variability in how well the antibodies can bind the antigens. B cells that produce Ab that better bind Ag are kept alive and proliferating, while ones that cannot bind as well are given cell death signals. At the end of the immune response, the B cells are better able to produce antibodies that bind the antigens than before. Pretty cool, huh?
Please Register or Log in to view the hidden image! This is why I am so interested in molecular biology.
Agreed! It’s interesting that you have described it as “evolution in our own cells”. I have often thought that the hypermutability of antibody genes in B cells and the subsequent selective propagation of variants encoding high-binding affinity antibodies is an example of Lamarckian evolution.
Yes, but I can't see the relevance of that to the genetics of antibody production mentioned in the opening post. Please Register or Log in to view the hidden image!
Just a small question.. Is the DNA ploymerase really error prone or is it programmed to create variability in the antibodies? How do we know the difference? This appears to be a case of brilliant design..the body creates different antibodies..learns which ones work...and keeps on producing those.
Variability in antibody-encoding genes is the result of error prone DNA polymerase. The fidelity of polymerases can be measured in vitro.
The mechanism is quite interesting as well, even though scientists are only beginning to get a full grasp of the system. A little more about the mechanism: Putting cytosine deamination to work Let's look at the genetic code first: Firstly, the genetic code emerged in such a way that cytosine deamination on a random pool of amino acids facilitates evolution. Described here. Secondly, cytosine deamination also does not result in any stop codon formation. Described here. Thirdly, Bollenbach et al. (2007) briefly describes a few more optimal features of the genetic code as discussed in more detail by Itzkovitz and Alon (2007). With a little background on the optimality of the genetic code, it is easier to appreciate the way the immune system makes use of these properties in order to generate antibodies. The vertebrate immune system exploits these optimal features of the genetic code by "putting cytosine deamination to work". Antibody diversification is crucial in limiting the frequency of environmentally acquired infections and thereby increasing the fitness of the organism. Initial diversification of antibodies is achieved by assembling variable (V), diversity (D) and joining (J) gene segments (V(D)J recombination) by non-homologous recombination. Further diversification is carried out by somatic hypermutation (SHM) and Class Switch Recombination. Central to the initiation to these diversification processes is the activation-induced cytosine deaminase (AID) protein. AID deaminates cytosine to uracil in single stranded DNA (ssDNA - arising during gene transcription) and is dependent on active gene transcription of the various antibody genes. The induced mutation is resolved by at least 4 pathways (Figure 4): 1) Copying of the base by high-fidelity polymerases during DNA replication. 2) Short-Patch Base Excision Repair (SP-BER) by uracil-DNA glycosylase removal and subsequent repair of the base. 3) Long-Patch Base Excision Repair (LP-BER) 4) Mismatch repair (MMR) VIEW IMAGE Figure 1: Activation induced cytosine deamination and the pathways involved in resolving the induced mutation. 1) Normal DNA replication results in a C:G→T:A transition. 2) Successful SP-BER resolves the mutation, however the recruitment of error-prone translesion polymerases results (e.g. REV1) in transversions (REV1; C:G→G:C) and transition. 3) LP-BER can also resolve the mutation, however recruitment of low-fidelity polymerases (e.g. Pol n) also causes transition and transversion mutations. 4) MMR repair can also resolve the mutation, however the recruitment of low-fidelity polymerases through this pathway is a major cause of A:T transitions. AID causes somatic hypermutation and its activity is limited to certain genetic regions of the immune system. When the system runs unchecked, mutations might be introduced into proto-oncogenes, resulting in possible cancerous growth. The system is controlled (Figure 2). The activity and gene expression of AID is controlled. The type of error-repair pathway and the subsequent recruitment of various low-fidelity polymerases determine the type of mutations after the repair process and these also seem to be controlled. Current research focuses on the mechanisms of control of downstream repair pathways and why this system is selectively targeted to the small region of antibody genes. Please Register or Log in to view the hidden image! Figure 2: Controlled variability of somatic hypermutation. Thus, the immune system exploits the properties the genetic code for the purpose of controlled variability. Teleological evolution where the immune system purposefully manipulates information by using the optimality of the genetic code, random variation and selection as a means to an end… antibody diversification. Is the system limited to vertabrates or can similar systems be found in other organisms. Cytosine deamninases are found in bacteria as well. Error-prone repair systems are also present. Will we discover an active system in bacteria that exploits the properties of the genetic code for the purpose of controlled variability under selective pressure? Will RecA and LexA play a part?
