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MICHAEL HEMANN: Chromosome segregation is actually
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visualized and chromosomes were visualized over 100 years ago.
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So again, over the turn of the 19th to the 20th century,
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people like Theodor Bovari used microscopic techniques
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that were emerging to be able to actually see the segregation
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or the movement of chromosomes from one cell to the other,
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or the separation of chromosomes as cells were dividing.
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Now these were visualizable entities.
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It wasn't clear at the time that these were actually
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structures that contain DNA or genetic material,
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although he did postulate that these did, in fact, contain
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genetic material, but that was shown only a little bit later.
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And you could see in a wide variety of organisms,
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including human cells, that all of these organisms
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had recognizable chromosomes.
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They could all be visualized, and actually,
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made some interesting observations that in cancer
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cells, like here on the bottom right,
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you actually saw missegregation of chromosomes.
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So you saw chromosomes that weren't
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neatly segregating into two daughter cells over mitosis.
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And that turns out to be really a characteristic of mitosis.
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So on the left here, we have chromosomes
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from a normal cell--
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so a normal human, if there's such a thing as a normal human.
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So this is a female with two X chromosomes.
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These chromosomes have all been stained with a technique called
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spectral karyotyping, which uniquely labels
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each chromosome with a specific color,
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so it's a good way to kind of map all of chromosome content.
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And so on the left here, we have a normal cell.
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On the right here, we have a cancer cell.
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This is one cell, and it has this colossal number
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of chromosomes--
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so too many chromosomes, lots of reorganized chromosomes,
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translocations, missing pieces.
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And again, this is something that
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was known over 100 years ago to be a characteristic of cancer
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cells that not only did they have lots of chromosomes,
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but they don't segregate their chromosomes really properly.
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So what are chromosomes?
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Well, as you know, chromosomes are
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a mixture of DNA and proteins.
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So DNA is wrapped around histones,
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which not only compacts DNA, but also regulates
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the transcription of genes.
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So it makes genes-- some genes off and some genes off.
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In a nucleus, it really looks like, during most of the cell
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cycle, a big bowl of spaghetti.
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So DNA is really filling the nucleus.
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It's really spread out.
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Even though it's still bound to histones,
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it's really disseminated throughout the entire nucleus--
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again, still compacted with nucleosomes.
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In the course of mitosis, you get condensation
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by many orders of magnitude into these recognizable chromosome
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structures, shown here to the right, where we're
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looking at two sister chromatids, so
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two replicated pieces of DNA, two double-stranded pieces
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of DNA, that have a centromere which, in most cases,
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is in the middle of a chromosome,
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although not always.
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I mean, it's called a centromere because it's
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sort of in the middle, but chromosomes can have
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centromeres towards one end.
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They can have them at the very end.
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In fact, all of mouse chromosomes
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are telocentric, meaning that the centromere is really
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at the very end of all of their chromosomes,
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next to the telomere, which is a chromosome end structure.
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So the telomere is a repeat sequence
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that essentially caps the end of a chromosome
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and protects it from degradation.
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It allows for the complete replication of the chromosome.
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Now these chromosomes are going to become visualizable
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during mitosis and in metaphase, where
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you have this condensation, which
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is really essential for the segregation of these
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into subsequent daughter cells.
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So we talked a little bit before about TH Morgan
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and Drosophila eye color.
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So red color is wild type, and white color is mutant.
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Really, the cool thing about this eye color
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was not just that you could actually--
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he could identify mutants and was really the first instance
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in a multicellular organism of the clear identification
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of a new mutant, but also, that it could be mapped
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to a particular chromosome.
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So we know from past lectures that this is an X-linked trait.
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And so, for the first time, you could actually
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map a particular phenotype to a particular chromosome to the X
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chromosome, or an alteration on the X chromosome.
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And this discovery in a lot of ways
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placed genes onto chromosomes-- introduced the idea
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that these segregating units were actually segregating
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phenotypes, and that the gene may
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be a physical entity on a physical structure in a cell.
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And certainly, in retrospect, is looked
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at as really the first clear example of mapping
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a gene to a physical unit.
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Subsequently, we've mapped a lot of phenotypes
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onto different Drosophila chromosomes,
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largely based on the ability to see that these are actually
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segregating in different ways, or independently
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from one another.
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So if a gene is actually independently segregating
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from one another, it suggests that it's actually
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on a distinct chromosomes.
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Now this can also occur if it's far enough
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away on the same chromosome, and we'll
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talk about recombination distance and linkage studies.
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But essentially, using this approach,
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we could start placing genes on chromosomes.
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So what do chromosomes look like in different organisms?
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Well, on the top left, we have people.
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So people have two copies of 23 chromosomes.
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This includes the X and Y chromosome,
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which we count sort of as one chromosome,
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or two versions of one chromosome,
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although they're substantially different.
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As you can see, chromosomes are numbered
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based on decreasing size, with the exception of the sex
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chromosomes.
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So chromosome 1 is the biggest and chromosome
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21 and 22 are the smallest.
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In this case, these are stained with Giemsa stain, which
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recognizes, essentially, condensed and decondensed
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chromosomes.
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And for years and years and years,
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people that do karyotype analysis or chromosome
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analysis in hospitals can easily recognize chromosomes
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not just by their length but by their banding patterns.
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So they can recognize translocations or movements
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of different chromosomes or loss of different chromosomes
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simply by this simple banding pattern and their ability
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to really recognize lots of details in this banding
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pattern.
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Now there's not a very good correlation
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between chromosome number and DNA content.
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So yeast have 16 chromosomes.
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This animal over on the right, here the muntjac
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which has a genome that is roughly
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the size of the human genome actually
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only has three chromosomes, so it
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has two copies of three chromosomes,
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so we see a total of six chromosomes here.
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And as you might expect, these chromosomes are huge.
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They're really, really big.
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They're the size of six of our chromosomes or so.
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So as we speciate, we develop different chromosome content
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and different chromosome sizes.
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An example of this is shown here.
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Here, we're looking at a comparison of human chromosomes
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and chimpanzees' chromosomes.
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And I think at first glance, what
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you can see is we're pretty similar to one another
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with very few exceptions.
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I mean, if you look at some of the length
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of these chromosomes, you'll see some differences
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and some differences in the length of the short arm, which
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are on one side of the centromere
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and the long arms which are on the other.
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But there's a major difference here,
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and that is, instead of our one chromosome 2,
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the chromosome material in chimpanzees
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is actually separated onto two distinct chromosomes.
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And this happens during speciation.
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That happens during evolution.
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And the development of new chromosomes
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actually makes it very difficult to, then, interbreed.
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It creates real problems in meiosis.
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And as we'll see, it's the ability
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of chromosomes to really synapse properly
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that allows them to be segregated properly,
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and so if you actually try to synapse two chromosomes to one
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chromosomes, you end up with significant problems.
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So this actually underlies a lot of sterility
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that we observe if different kinds of species
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mate in their F1 generation because they're
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unable to undergo proper meiosis.
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