Goldilocks Principle

00:00 So, I call this lecture the Goldilocks principle because it all has to do with Goldilocks, the story where we've got three bowls of porridge and one just has to be just right. Gene expression is just the same. We have too much gene expression, overexpression or we have not enough gene expression. That's the root of pretty much all genetic disorders. So, why not call it the Goldilocks principle? The key here then is having the right amount of gene products but how is it that we regulate the amount of gene product? So, this is a question that you should be able to answer from having seen our previous lectures. But there are a few more things that we'll consider. So, let's take a look at what we've seen already, things we already know. We know that epigenetic factors certainly have an impact on whether a gene can be expressed or not. Is the gene hidden by its epigenetic coding or are we able to actually transcribe and translate the genes? Now, epigenetic factors are sometimes heritable, we're learning but sometimes, they may be applied and removed as we'll see in some examples in this lecture. You also can probably predict that one of the things that we'll recognize as affecting the amount of gene expression or the amount of gene product is the regulation of transcription. Recall that there are tons of different proteins involved in moderating that process as well as RNA processing and translation. Of course, those are also coded for by genes that produce proteins.

01:43 So, you could have problems with the regulatory proteins which actually affect the expression of the gene itself.

01:51 So, we have the multifactorial concept there again. But all of these places are means where we could regulate the amount of gene expression and potentially impact the phenotypic expression unless you have some genetic disorder.

02:09 We also know that there are many players involved in the post translational events when we fold a protein and make it into the shape that it needs to be to do its job. So, the proteins that regulate that will certainly have an impact. Finally, we can regulate the amount of gene product around simply by regulating how long it stays around.

02:34 For example, when does the thrash disposal systems that we've talked about in our cell and molecular class, when did those come along and gobble up the proteins and removed them from a place? Either way, we know that when there's too much or too little gene product, problems come into play. So, unbalanced expression is one of the main reasons that we could have an imbalance. So, other than looking at our regular regulatory issues, we could have unbalanced expression. That can result either fairly randomly from expression of both alleles.

03:15 So, let's start at the basics. We've got a blue chromosome and a pink chromosome. One comes from the maternal input.

03:21 One comes from the paternal input. In a normal situation, you would expect that both alleles are expressed at the same rate. Thus, we have an equal amount of gene product that you see up in the top right. So what happens though if one gene is not expressed at the same rate as the other gene? We could have an imbalance in gene expression.

03:45 Sometimes that imbalance is just right. But sometimes it's not right. When it becomes not right, then we again have a genetic disorder show up that we might be able to trace back to its origins.

04:01 Now, we also can have monoallelic expression.

04:05 That is only one allele is expressed.

04:08 And we're not talking about the XN activation where one is crumpled up but for some reason, and it could be random, we may only have expression of one allele.

04:19 So, let's look at some of the ways in which we might get monoallelic expression.

04:26 First of all, we could have a random choice, as I just said, it could happen because of genomic imprinting, and we'll take a look at both of those cases, as well as it happening from X-inactivation.

04:40 So, these are three distinct ways that we may end up with only one allele being expressed even though both of them are actually there.

04:49 So, when we look at monoallelic expression being a random choice, there are two possibilities that have surfaced.

04:59 One of those is allelic silencing where literally, one allele is silenced by epigenetic mechanisms.

05:07 So, either we have DNA methylation or histone modification or one of the epigenetic mechanisms that literally makes the DNA inaccessible to the transcriptional process.

05:19 The other means we could have is by somatic rearrangement.

05:23 This is one of those places where we talked about being, having an inversion.

05:28 Let's say the inversion happened right within the genes so the break point for one of the ends of the inversion is right in the middle of the gene and that piece of DNA flips and is inserted back in.

05:39 Now, we've broken a gene and so randomly, that gene may no longer be able to be expressed, leaving only one allele or monoallelic condition.