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Lecture 24

Lecture 24- Genetic dissection of complex traits

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University of Toronto St. George
Human Biology
Christian Campbell

Thursday, April 2, 2009 - To day is one of his fav o u ri te le ctures bease it brin gs everythin g together that weve learned so far this term. HMB265 Lecture 24 Why Some Things are Bigger than Others. Today we will look at how one dissects things like size in a tomato, dogs and even humans using genetics, so genetic dissection of complex traits. - Before we start on that, let us take a look at where weve been & where were going. So lets take stock of where weve been, what we have seen so far this term. We started with Mendel & he was looking at traits with simple modes of inheritance, simple bifurcating traits, you either had 1 aspect of the trait or another aspect of the trait, simple qualitative traits & that is what we saw at the beginning of term, these simple qualitative traits. - What we had to do over the course of the last lecture since Lecture 14 was to elaborate on Mendels basic laws & the point he wants to make is that Mendel is still there, the laws he established are still there but we had to elaborate on them to accommodate some of the biology we know is st going on. We had to accommodate 1 of all, concepts such as epitasis, where 1 gene is modifying the effect of another but Mendel was still there. We moved on doing other modifications such as incomplete dominance where heterozygotes show an intermediary phenotype but Mendel is still there. Then we worked on to linkage & we showed that Mendel here was a little bit wrong. He had looked at traits that were unlinked so the idea of complete independent assortment applied to a good many traits but we knew that it didn't apply to all traits, the traits could be linked together by virtue of the fact that the genes controlling them were linked together on chromosomes that is linkage groups. Even still, the basic premises of Mendelian genetics were still there, the idea that genes segregated & reunited in the offspring gave rise to traits one observed in 1 generation to the next. The idea of allelic diversity was still there. - Finally what we touched on was dealing with this level of complexity, not qualitative traits but quantitative traits, traits that showed continuous variation & what we showed was underpinning this variation, we could still explain things in Mendelian terms. We still saw the segregation of alleles that were controlling the traits, we saw that it could be a good many loci of segregating alleles that control those traits or a few loci controlling those traits but the effects of those loci, that is, the different phenotypic classes were masked by the environment. - That is where we finished: Tryin g to disco v er the genes that underpinned the quantitative traits b/c Mendel was still there so what we were interested in was to try & figure out how much the variation is attributable to genetic variation & once we figure that out & we figure out that trait is highly heritable that is attributable to additive effects, attributable effective to incomplete dominance with 2 alleles segregating at a locus, how one can go about dissecting that through QTL analysis, Quantitative Trait Locus analysis. - We saw that all we had to do was to have 2 dissimilar & relative to each other inbred parents mate together, create a F1 that showed an intermediary trait just as one expects in incomplete dominance, self that individual or the progeny so derived to give rise to an F2 population where the trait & the alleles are segregating. What we did in the last lecture then on Tuesday was to walk through the steps necessary to establish a correlation between where the alleles were segregating and where the trait was segregating and we finished with some diagram. - We are lo o ikn g acros s a lin kage gro u ,p acros s here at the bot tom looking across a linkage group with a variety of different loci. We established on the basis of a statistic, the likelihood of association between a given locus like the L or the A locus & the trait as demonstrated by the test statistic. Some people said that this QTL interval, what does that mean? QTL means quantitative trait locus interval. Because he is using statistics, he can only state with a certain amount of probability that thats where the locus is. - If he establishes a LOD score of 3 as his cut-off value, he can state with 99.9% certainty that the locus that is controlling the trait lies between the two dotted lines, with the peak in the middle is the most likely location for the locus controlling the trait. - Some of us walked away thinking probably wait why isnt it just a great bit spike here of a LOD score for perfect association b/w the locus & the trait. The reason for that, why you have a mountain rather than a spike is b/c down here, these genes Q B N & J are linked physically on a chromosome to the locus that is controlling the trait. So by virtue of being linked, it means every now & then the segregation of the alleles at that locus, actually the more often than not, the closer they are to the locus controlling the trait, they are going to look like theyre controlling the trait as well but theyre just nearby. It is like guilt by association. - Weve seen this movie before, the F & H locus are very close by, we know that infrequently, crossovers can happen b/w F & H, b/w non-sister chromatids of homologous chromosomes resulting in a recombination event well see right here. Most of the time were going to have F & H, f & h travelling along together, the parental types & by virtue of that fact, what you end up with them is a mountain b/c Q, the alleles segregating at Q are co-segregating with alleles at L b/c theyre linked together & that means Q every now & then looks like it controls the trait but not perfectly so b/c there will be recombination events every now & then b/w Q and L so the association of the alleles segregating at Q is not perfect with regards to how the trait is segregating. - That is where we finished. What he wants us to do is if this stillsounds odd is over the weekend, sit down & look through Lecture 22 how we worked through the various steps to get to this particular graph. He will assume we have good knowledge of this & now we discuss if people really use this. - Do people use this approach to dissect genetic traits? That is todays lecture. Today what were going to do is were going to look at the slide. Today is to serve as an example to link the stuff we see in the news and what we read in newspaper. Back to the topic at hand now, do people really do this? - Of course they do, and he will start with plants because that is where we ended in our last lecture. We stick with the tomato story and say to us that just as we worked things through using the example last week, this is precisely what people like Steve does in real life to identify then genes controlling fruit size in tomato. They have genetically dissected the basis of tomato fruit size. - Step 1 is the exa ct same as what we described last le cture. They generated a QTL map, a quantitative trait locus map. - We looked at 1 linkage group, here are all the linkage groups, well most of them from tomato, at least those with the QTL on them, linkage group 1, 2, 3, 4, 7,8 and 11. We have a number of different linkage groups and note each have a QTL interval for fruit weight on them that is what FW stands for. This is a rather imprecise one here, the confidence interval is quite long covering a huge chunk of the linkage group. The linkage group is effectively a genetic map of a chromosome. - What he wants to do today is to focus on one of the loci they identified as a quantitative trait locus controlling this particular trait. - Note that there are a number of different QTL controlling this trait, there are a number of genes then that control fruit size in tomato but they focused on one of them and that will be our focus today. It is on linkage group number 2 and that is on the bottom, it is fw2.2. That is what well focus on today. - Because they were able to zoom in on this particular QTL, the way they zoomed in on this QTL was by making use of the segregating F2 population which they used to construct the QTL map to create what are known as recombinant inbred lines, RILs. - He willshow us inbreeding down a lineage in a diagram illustrating single line of descent. - What he wants to do is to come back to point 6 in the slide again in a bit.
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