Why do we need chromosomes?

Most cells in our bodies contain 46 separate long DNA strings that spend most of their time in what appears to be a tangled mess – in a round sort of shape we know as the nucleus. Then lo and behold, these long strings fold up and become chromosomes. Why do they do that?

Bill Earnshaw’s lab at Edinburgh University does some amazing work with chromosomes and cell division. He can explain very elegantly why we need chromosomes.

The DNA makes a copy of itself before the cell divides into two. The chromosomes help make sure each new daughter cell gets an identical copy of this DNA. It’s easier to divide tangled strings into two if you untangle them and roll them up into balls first.

Here it is in real life:

In the video you can see the chromosomes line up along the middle of the dividing cell (the “equator” or “metaphase plate”). When they’re all lined up correctly (this stage is “metaphase”) the chromosomes can split in two halves which separate. The whole cycle of chromosome growth and division is called “mitosis”.

DNA carries genes that make up the blueprint that’s responsible for making every cell, every tissue, every organ work correctly. So it’s important we have the right set of genes.

Cells divide a lot – millions of our cells divide every minute so it’s important that the DNA is shared precisely each time. Mistakes can cause the new daughter cells to misfunction. These cells can become cancerous or produce babies with genetic disease. Usually the cell watches out for these mistakes and self-destructs. But not always. Research helps us understand these processes, how they can go wrong, and work out ways to prevent or fix these mistakes.

 

Cross-posted to chromosomesandcancer.com.

Mitosis – fun with modelling clay

Mitosis has to be one of the more beautiful things in nature. It’s a choreographed dance of the chromosomes. It’s so small that we can’t see it without a microscope, but it goes on in our bodies billions of times a day.

DNA is a very long molecule made up of the genetic alphabet (which has four letters: A, C, G, T). A gene is made of a certain sequence of DNA letters (or bases) and spells out an instruction for a step in the complex workings of our bodies (such as the structure of insulin). The genes are strung together along the chromosome, and each cell has a set of chromosomes. For our bodies to grow, these cells need to make copies of themselves. The problem of how to distribute the copied chromosomes evenly to the two “daughter cells” is handled very elegantly.

Human metaphase chromosomes stained with Giemsa (unbanded). The two halves of each chromosome are copies of each other.

Mitosis is the solution. Mitosis is broken up into a series of phases: interphase, prophase, metaphase, anaphase, telophase. You could add prometaphase: the part of prophase between the nuclear membrane breaking down and metaphase (where the chromosomes line up at the metaphase plate).

Now follow the captions under the pictures.

The interphase nucleus - the DNA from all the chromosomes intertwined with each other is represented by grey modelling clay. (Actually it seems that the chromosomes stay in relatively distinct domains - but under the microscope they appear as one entity.)

The interphase nucleus.   The DNA from all the chromosomes, intermingled with each other, is represented by grey modelling clay. (Actually it seems that the chromosomes stay in relatively distinct domains – but under the microscope they appear as one entity.) The DNA in the interphase nucleus copies itself as the cell grows.

 

The DNA in the nucleus starts to package and take shape as prophase chromosomes.

The DNA in the nucleus starts to coil up in a pre-determined order and take shape as prophase chromosomes.

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The DNA folds up in a pre-determined order to make recognisable chromosomes. When the cell is ready to divide each chromosome has two chromatids or identical halves, joined at the centromere.

The DNA folds up further to make recognisable chromosomes. When the cell is ready to divide each chromosome has two chromatids or identical halves, joined at the centromere.

 

At metaphase the chromosomes meet in the middle of the cell at the metaphase plate. Then as the cell divides to become two daughter cells, the two halves of the centromere split and travel along the microtubules in opposite directions, pulling the two halves of the chromosome behind them.

Metaphase - the chromosomes line up in the centre of the cell at the metaphase plate. They are attached by their centromeres to microtubules which stretch across the cell.

Metaphase – the chromosomes line up in the centre of the cell at the metaphase plate. They are attached by their centromeres to microtubules which stretch across the cell.

At anaphase the two chromatids (half chromosomes) become the new chromosomes as they separate and move in opposite directions along the microtubules.

At anaphase the two chromatids (half chromosomes) become the new chromosomes as they separate and move in opposite directions along the microtubules.

 

The chromosomes start to unravel to form the two new daughter interphase nuclei. The cell membrane (the outer covering) pinches at the centre and the one cell finally becomes two (cytokinesis).

The chromosomes start to uncoil to form the two new daughter nuclei – telophase. The cell membrane (the outer covering) pinches at the centre (cytokinesis).

The cell membrane pinches at the centre (cytokinesis) so the cell finally becomes two cells.

Cytokinesis finishes and we have two new cells in interphase.

 

If a chemical that destroys the microtubules is added to a laboratory culture, the chromosomes are stopped at metaphase. Cytogeneticists (chromosome scientists) use this technique to get enough metaphase chromosomes for analysis. Chromosome banding helps recognise the chromosomes and identify any changes when an abnormality is suspected. Of course, the cell is also full of other organelles that have to be shared between the new cells.

The modelling clay images above are from my claymation showing mitosis. Modelling clay is a great medium for demonstrating and thinking about how things work, move and change. For the claymation I used a phone camera resting face down on a glass coffee table over the models.

Cross-posted to www.chromosomesandcancer.com.

How some rediscovered 75-year-old research on maize helps us understand cancer

Barbara McClintock published a paper describing the breakage-fusion-bridge (BFB) cycle in 1939. She studied the genetics of maize, and many of her ideas were well before their time. Like many such profound leaps in thinking, the BFB cycle took a long time to catch on. She wrote in 1973, “I stopped publishing detailed reports long ago when I realized, and acutely, the extent of disinterest and lack of confidence in the conclusions I was drawing …One must await the right time for conceptual change.” Her work was appreciated much later and she was awarded a Nobel Prize in 1983 for her discovery of “jumping genes“.

Fast forward 75 years and we have an unexpected benefit of this seemingly obscure plant research. It can help us understand some of the mechanisms involved in cancer. The rediscovered breakage-fusion-bridge cycle can make cancer very aggressive, and it may be much more common than we think. Centromeres (see below) are the key to the BFB cycle, but  centromeres are largely overlooked, both in research and diagnostics.

This is how it works.

The breakage-fusion-bridge cycle is one way that chromosome division can go wrong. Very wrong, in the sense that it can cause the chromosomes to keep changing, and this can cause cancer. I’ve put together this animation, which illustrates the breakage-fusion-bridge cycle. There’s a summary of normal chromosome division on my blog, chromosomesandcancer.com.

A human chromosome with two centromeres is abnormal. One way this can happen is when the telomeres become degraded (see a previous post). Chromosomes with two centromeres are not unusual in cancer cells. In fact they’re probably a lot more common than we think, because in both research and diagnostic labs the centromeres are usually not looked at.

To recap, a normal chromosome has one centromere. Before the chromosome divides, the two identical halves (chromatids) are held together at the centromere. When the chromosome divides the centromere splits into two halves, the chromatids become the new chromosomes, and the centromeres take the two new chromosomes in different directions into the two new daughter cells.

So what happens if there are two centromeres? If they’re both aligned so that they head in the same direction it’s not a problem – together they take a complete new chromosome with them. The closer the centromeres are together the more likely this is.

Now follow the pictures and their captions. These describe chromosome division in an abnormal chromosome with two centromeres. In particular, follow the yellow dots.

A twist between the two centromeres when the chromosomes align ready for chromosome division.
If the two centromeres on a chromosome go in the same direction there’s no problem. But if there’s a twist between the two centromeres when the chromosomes align ready for chromosome division….
....then, when the two halves of each centromere separate they head off in different directions.
….then, when the two halves of each centromere separate they go in opposite directions. We have a “bridge” spanning the gap between the two centromeres.
The bit of chromosome between them gets stretched and can break.
The bridge is stretched and can break.
The broken chromosomes in the new cell join together - the top daughter cell gets an extra copy of the yellow gene. The bottom cell loses this copy of yellow gene.
The broken chromosomes in the new cell join together – the top daughter cell gets an extra copy of the yellow gene. The bottom cell loses this copy of the yellow gene.
The new chromosome copies itself to make two equal halves.
The new chromosome copies itself to make two identical chromatids.
If this process repeats..
If this process repeats..
Fusion of the broken bits of chromosome in the top cell.
Fusion of the broken pieces creates a chromosome with four copies of the yellow gene.
After replication - the new chromosome with four copies of the yellow gene courtesy of the breakage-fusion-bridge cycle.
After replication.

If the yellow gene in the pictures is a cancer gene (“oncogene”) the cell with extra copies might grow and multiply faster than its neighbors. We call this natural selection – the cells that can grow faster than their neighbors become more common, which means the genetic change causing that is undergoing “positive selection”. Yes, the cells in our body can evolve and we know this best as cancer.

All this change happens between the two centromeres where the bridge forms. So if we find a chromosome with this type of change on one side of the centromere only, it’s a clue that this might have been caused by the breakage-fusion-bridge cycle.

Many (perhaps most) images demonstrating the BFB cycle show a different version – where the abnormal chromosome is created by breakage and joining together of the two chromatids of one chromosome. Check this out on Google Images (search for breakage-fusion-bridge). But I think the version I’ve shown here – where two different chromosomes join – is probably more common. It’s the more common version in my experience with acute myeloid leukemia.

 

(This is a modified version of a post in my blog.)

Further Reading:

B. McClintock 1939. The Behavior in Successive Nuclear Divisions of a Chromosome Broken at Meiosis. Proc Natl Acad Sci U S A. 1939 August; 25(8): 405–416.

M. Kinsella and V. Bafna 2012. Combinatorics of the Breakage-Fusion-Bridge Mechanism. J Comput Biol. 2012 June; 19(6): 662–678.

R. MacKinnon and L. Campbell 2011. The Role of Dicentric Chromosome Formation and Secondary Centromere Deletion in the Evolution of Myeloid Malignancy. Genetics Research InternationalVolume 2011 (2011), Article ID 643628.