Questions Around Allelic Exclusion, 30 Years On

It’s 28 years since I studied allelic exclusion in B lymphocytes as my paper based undergrad’ thesis. I kind of fell upon the concept, as it always bothered me from the first days of understanding simple Mendelian genetics – how does it all work with two copies of a gene yet only one phenotype?

Well Mendel of course, cheated. He actually ignored strains of peas whose flowers bred through to pink, instead of those which bred pure white or red. Genetics is always throwing up complexity around some central simplicities, and as with the Human Genome Project, scientists go off on keep-it-stupid-simple at their hazard.

In allelic exclusion in certain types of  white blood cells, there is some very interesting genetic engineering, and sorry dear creationist, you can see evolution happening in your own bodies if you care to study the molecular mechanisms. At some point a white blood cell decides                                                                                                                                                                                                                                   to make one very specific antibody which has the purpose of             very specifically locking onto a potential  disease causing agent. This is then locked and in effect it becomes a memory cell if you like, which can then explode in a clonal type way to produce thousands of these cells all of which are identical to fight a disease currently threatening the body, or doing so in future. Earlier on in the story, the cells have undergone some degree of evolution, firstly by being selected as fairly good matches for that ‘pathogen’ or antigen to be more accurate, and then having to select which one of two versions of the gene for the antibody will be the one which is most suited to the job at hand after in fact the cell induces some very specific mutations, or internatl genetic engineering, to alter small parts of the antibody such that it may become more specific and thereby the antibodies will bind better and discriminate between this specific threat and others in a manner much enhanced over the earlier incarnation of the cell line.

So one gene gets switched roundly off, while the other copy, which is a little different due to this ‘hyper mutation’ is kept for the life of the new cell line. If i remember correctly, there was only one iteration of this process, but of course it occurs over a population of white B lymphocytes and other related antibody producing cells, so that a diversity is then honed down into a more targeted set of cells which can tackle disease better. So we see natural selection at work, every day , in our own bodies with mechanisms of molecular directed evolution to boot!

Now this was thought to be a very specific mechanism, the exclusion of one of the two copies from further use in the cell. However back to Mendel. It seems to be very wasteful to have one copy of the gene which is recessive, or presumably non functional? White flowers it seems are default no colour when two copies of the white, failed gene are present. It just seems a waste of space.

Well in fact recent research amongst relatively inbred populations including Iceland and an area in Pakistan, show that in fact humans in such small gene pools harbour upto 7% inactive gene copies. It may seem that prevalence then of genetic diseases would be much higher, but althouugh some typical genetic linked diseases like Huntingdons are present, there is actually not a correspondingly higher rate of disease in accordance with the inbreeding and this high percentage of ‘knocked out’ genes.

Here we see again that a simple route can reveal complexities and the golden rules can and are broken, wihtout perhaps the exeptions quite proving the rule. We find that a gene in the genome, on the chromosome, can be swithced on and off intermittantly, or more locked away and this can vary between copies, sometimes the paternal is less likely to be switched on than the maternal copy. The simply methylation of chromosomal DNA can affect this. Also the gene product need not be a protein, but can be an intermediary control element. And if there is a final protien as in the good old central dogma of genetics, then it can vary in how it is constructed from the one gene, or be made up of several genes spliced together at the messenger RNA level. 

Oh dear, Genetics is big and scary and the Human Genome Project to some extent, only confused us more. There were fewer genes than expected, and a now it seems there may be more inactive, fautly genes that first thought. Also there may be redundancy of alleles, or multiple alleles of the same gene, or perhaps gene products can be cobbled together to make up for a K/O’ed gene at the mRNA level. It suddenly became important to study diversity between individual genomes so as to try and understand what was going on. 

From my point of view then I always said that in Genetics and molecular biology, there is simplicity to be found in diversity, and that the abnormal informs the normal. There is a fundamental truth that in studying one fairly obscure genetic phenomenon, we find a universal truth, yet we cannot understand a universal trith fully without considering diversity.

Big science has kind of speeded things up, but also quite possibly used up huge resources in uncovering issues which were already there as in the last paragraph . We need to look at the detail but also how varied each detail is. So if you follow one obscure detail, like allelic exclusion in B cells, then you find out a lot about it, in fact so much that in this case specifically, it seems it is just an obscure mechanism . for time being. If you give yourself a bigger job, then yes you get more done in terms of this diveristy, but you are building a bigger stick to beat yourself with as that diversity then starts to obscure the universality in mechanisms. However Big Science came with a lot of public and private funding so we cannot complain from that point of view, and a lot of processes which were tedious and manual when I was working in labs (with the first commercially available multi well PCR thermal cycler with digital control) have been either fully- or semi/automated and results are as likely to be read on a computer screen than in a ‘petri dish’so to speak.

The older, more patient and pedantic me would suit being a scientist today because I am quite computer literate and like solving puzzles,. At the same time being locked into using standard equipment means that you perhaps loose some pioneer spirit and perhaps come up with less new technique innovation, which is also very enabling in terms of being able to do new things, if not do the same thing thousands of times over accurately and automated. 

We come back to the whole simple argument which is really about sex. Why have diploid organisms which breed sexually? Well in fact those industrious and ingenious little B cells have the answer. We need diversity to survive and evolve. Without diversity there would be no real selective evolution, one species would tend to get whiped out, as we saw with for example the potatoe blight of the 1800s which was from all plants stemming from a tiny number  brought back from S. America. We need sexual reproduction and sexes because it means we can recombine good survival packages of genes to then meet the challenges of the environment. Sex speeds up evolution by this mixing up of genes too. Some new combinations fall by the way side, while other quire surprising genes come to be quite common, such as the odd case of sickle cell anemia, a simple point mutation, which you would have thought would be bread out due to the higher morbiitiy and mortality of having the double dose. But the single dose confers a protection from malaria, which hides in red blood corpuscles, which then split open upon infection. Here we see a perfect example of the opposite of my thesis area, where there is no exlcusion what so ever, there is a neutral inclusion of both gene expressions. 

 I could hypothesise then that we will find that some gene alleles have one favoured all or most of the time, while others just arent important enough. Some alleles can be compensated for by other gene alleles or qausi alleles. Some gene alleles have one of the pair long term down tuned  via methylations, and that can be tissue specific. Some genes may well be turned more on at one of the pair copies. Some genes will be then later tuned or eliminated at their RNA level as far as getting stuck onto the ribosome protein factories. Sometimes we may need multiple copies of the gene on at any time to make enough protein or gene product. 

Allelic exclusuion in the context of a secually reproducing multicellular  organism is a high risk strategy in some 

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         

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