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BIO240H Lecture 24.doc

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Jennifer Harris

Lecture 12: From Genome to Phenome Slide 1 - So elaboration of the central dogma. Where are we? - One of the things he hasn’t focused on in its relation to DNA, RNA and a protein is that obviously there is cross-talk between the different pathways in terms of their regulation. In fact the metabolome can feed back and modulate things like the RNA pool even the regulation of the DNA chromatin structure itself. The interactome feeds back and so on. Moreover things feed forward in those particular pools as well so there’s a lot of complexity. - How does this fit into the big picture? He wants to see how one goes from all of this to the phenome the physical thing you see in front of you and that is what we’re ultimately interested in, how all of these things are integrated to give rise to the diversity of organisms we see around us. - We’re going to just recap everything covered in the past 11 lecture and talk about the implications of this in giving rise to diversity of the phenome. Introduce concept of genetics and briefly talk about science fiction and science fact. Slide 2 - Over the term we’ve looked at this elaboration of the central dogma and we’ve talked about the generation of the phenome. We’ve gone from genomes to phenomes. We’ve taken a look at the various steps involved in generating an organism like ourselves. Slide 3 - We started ourselves with the role of the transcriptome and deriving the variety of transcripts that are present within the genome and we talked about how there were differences not just between very different organisms and within organism between cell types. - We talked about the role the epigenome plays in giving rise to differences in the transcriptome. Slide 4 - For example, here gene B active in the 4 year old Malcolm Campbell and gene D inactive. This changes dramatically as we go from the young chap to the ancient one on the right side. Slide 5 - We talked about the sort of things influencing this and they are the transcription factors, the gene specific transcription factors, the sequence specific transcription factors, the gene regulatory proteins, all one and the same. Slide 6 - This is what the transcriptome is going to look like and ultimately we’re going to create a proteome and the proteome will give rise to these differences. Slide 7 - Finally, we looked at how the proteins interact in the interactome and how that is going to give rise to those sort of differences. Slide 8 - The one thing that he finds talking to students at the end of the course is the wow factor in that all of these things give rise to differences in organisms, it's a wonder that we even get organisms looking alike at all with the sheer number of steps for possible variations to occur. - That begs the question, where do the differences come from? We know where the differences come from because we missed out an important element in our consideration of genome to phenome. Slide 9 - We missed out on MENDEL. - When he was at the monastery, he was sent off to solve a particular problem that the monks were having problems with regards to organisms breeding true. The head of the monastery was interested mainly in sheep growing nearby. Gregor was sent off to Vienna to study subjects that might help him out in solving this problem so that to ensure that organisms farmers were growing for particular reasons, sheep and their wool for instance, were always bred true. The problem was that animals didn’t always breed true, breeding two perfectly good sheep together could produce an offspring that had terrible wool production, why was that? Why did in some pairings, some things work whereas other pairings failed? - He was sent off to study with the best people like Dr. Doppler for studying physics (Doppler effect guy). He studied lots of different subjects, brought that information back to the Augustinian monastery and proceeded to plant particular plants: peas, garden peas. Slide 10 - He published some astonishing results he learned about his garden peas at 1865 at the age of 43. In doing so he became the father of modern genetics. - He was looking at these garden peas in the slide. He was looking at alternative traits or alternate pairs of traits in garden peas. They are called antagonistic pairs like long and short stems, green versus yellow pods and purple versus yellow flowers. Slide 11 Alleles Alleles - He described these particular antagonistic pairs, he didn’t use the word genes but he called the differences between them, alleles. These variant forms were called alleles. An allele is a variant at a genetic locus. We will touch on the source briefly on the source of variation between antagonistic pairs, the source of variations. What is the source of this variation? Slide 13 - We will look at round versus wrinkled peas. - We won’t look too much at dominant versus recessive traits except here, it turns out that the dominant allele in this case is the round one. It gives rise to a functional starch branching enzyme which converts unbranched starch to branched starch and this branched starch just the way in which it retains water, allows for a nice round pea. - The point he wants to make from this slide is that, that allele does something molecular, it does something biochemical, it encodes an enzyme that does a particular job that gives rise to a visible trait. - The recessive allele is effectively nonfunctional, it has an inactive starch branching enzyme and as a consequence, unbranched starch isn’t converted to branched starch so the water retention properties of that results in a wrinkled pea. - We not only have a molecular explanation for the trait but we have a molecular explanation for the antagonistic pair, one enzyme is functional, the other is dysfunctional. That is the source for these traits, the source of the variation that we see in nature, it's these simple molecular explanations. It all comes back to what we learned and that it comes down to things like gene expression and the elaboration of the central dogma, we will explore this idea with alleles. Slide 14 - Imagine that we have a normal functional gene, it has a promoter, which comprises of the minimal promoter and the gene regulatory sequences, a coding sequence beginning with ATG, finishing with TGA, an intron in the middle, they’re all labeled. - In the process of transcription, we’re going to make the immature transcript first, that will be processed to get rid of the intron, add the poly-A tail and the 5’ cap giving rise to mature RNA and then through translation, that will be made into a nascent protein which folds through co-translational folding to give rise to a nice folded protein in the bottom. That gives rise to function. - This is what we saw with Mendel’s round pea allele, let’s consider the sources of the dysfunctional or non functional allele. Slide 15 - There is our wild type allele and here what we do is change a single nucleotide in the coding sequence and that produces a transcript that will get spliced and processed, and there is our same nucleotide change and that will change a glycine to a glutamate residue. What may happen as a consequence of that is at the end of that, perhaps the glycine was required for a particular secondary structure for that enzyme, is that we may end up with an unhappy protein at the end and no or altered function. Slide 16 - Here we see that just by changing the nucleotide sequence and just changing something we’ve learned about this term, (protein folding) we can ultimately change the function that arises from that. There we have a misfolded protein and altered function. Slide 17 - Here is another example where we introduce another nucleotide change that gives rise to a premature stop codon which is nicely transcribed and processed and during translation, we’ll end up with a truncated protein being made. There is the half frowny face and has altered function - We can keep doing this with many other examples as we can imagine. Slide 18 - Here he has changed a stop codon into something that is not a stop codon. So now, we create a transcript and translation proceeds where translation wouldn’t proceed normally giving rise to an elongated protein which again, may have altered function, that would be mutant allele 3. Slide 19 - Another example is that we alter the intron so that it is no longer spliced properly so we have mis-splicing that occurs and as a consequence we get all sorts of crap produced, lots of garbage without a function at all in the organism. Slide 20 - Here we’re changing a nucleotide sequence in a gene regulatory region in the promoter and what we end up with here is some sort of altered transcription, in his example it is no transcription whatsoever so no RNA therefore no protein and no function. Slide 21 - In the end, what we end up with is a bunch of different alleles and they are produced merely on the basis of single nucleotide changes to DNA structure resulting through the central dogma and the things we learned associated with the elaborated central dogma with varied function at the end. All of these different steps we learned about over the course of the term can give rise ultimately, to altered function and therefore the diversity of the organisms we see around us. - Some of us might be scratching our head and saying that can’t possibly be true for everything we’ve covered and he would argue that everything we’ve covered can have some sort of molecular variant that can give rise to different function. Movie playing - This example is being presented in this movie. - What we’re looking at is we’re going to ubiquinate that etaxin (not sure if this is what he really said) molecule there. There’s our ubiquitin carri
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