DNA mutations
By Alex | August 11, 2008
We’ve all heard of them. We also know it’s really bad if mutations occur. And if you remember the works - from DNA to RNA to protein to overall body functioning, you’ll understand how even the smallest change (1 nucleotide even) in the DNA can have CATASTROPHIC consequences at the protein level!!!
When do mutations occur?
Errors in the DNA (aka mutations) occur when the DNA duplicates. And this happens when a cell divides. When a DNA molecule is copied into a new DNA molecule which will go into the future daughter cell, the duplication must be perfect, each nucleotide must be copied as it is in the mother cell DNA.
And of course since we continue to exist as humans and not mammals with 3 legs and lizard tails, it’s because our DNA is not altered and very few mutations occur in our cells.
How is our DNA preserved and protected from mutations?
There are several ways in which our cells do that. First the redundancy of the genetic code - remember it from the last post on codons? That’s how!
Then there’s this really cool enzyme - DNA polymerase which copies DNA into DNA. This enzyme has a proofreading ability - meaning that it can detect if it has made a mistake and inserted a different nucleotide in the new DNA. If so she can cut out the wrong nucleotide and replace it with the correct one. Pretty amazin’, right?
Are there different types of mutations?
Yup. If one single nucleotide is mutated (an A replaced with a G for ex.) it’s called a point mutation. If larger (than 1 nucleotide)fragments of DNA are inserted/deleted it’s called an insertion/deletion.
How does a point mutation affect the protein?
Case 1: Silent mutation = mutation with no effect
Say you’ve got TCT in a DNA sequence. This becomes UCU in the mRNA. If the final T is mutated into a G then the mRNA sequence will be UCG. So UCU->UCG. The UCU codon encodes serine. And so does UCG!!! Go figure! So this is a lucky one. The amino acid is unchanged, there’s no effect on the protein! Phew!
Case 2: Missense mutation = mutation which changes the amino acid
That’s an easy one. You can figure out an ex. for this one! This type of mutation can have mild or sever effects on the protein. If the new amino acid is somewhat similar in nature and size with the old one the protein can still be functional. If however the mutation has affected a key amino acid in the protein, then things are not so rosy!
Case 3: Nonsense mutations = mutations which truncate the protein
Remember the stop codons? Those which tell the ribosomes to stop making the proteins? Well if a mutation leads to a STOP codon (UAA, UAG, UGA) to form at the wrong place, then the protein will end prematurely and the chances of it being functional are very, very small!
Image taken from this Stanford website on Huntington disease.
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Codons and amino acids
By Alex | July 15, 2008
In my previous post I was telling you about how tRNA helps ribosomes match a certain 3 nucleotide sequence (codon) on the mRNA with an amino acid.
Amino acids are like beads in a necklace - the protein. They are found in the cell cytoplasm and are brought to the ribosome by the tRNA. There are 20 amino acids and you can find their names on wiki. Some of these are essential, meaning that the body cannot make these from other chemical molecules. We need to get them from food. Hence the need for a proper nutrition!!!
Now let’s do some maths!
There are 4 nucleotides in the mRNA: A, C, G, T. So with these 4 you can build 64 combinations of 3 nucleotides. So why aren’t there 64 amino acids and only 20? Well, this is called the redundancy of the genetic code: more than 1 codon corresponds to the same amino acid. Take a look at this image from here.
What is the redundancy of the genetic code?
Let’s take leucine. Look at 1 o’clock on this chart. If you begin in the middle of the chart with the big U, continue with the small U, you’ll see that both A and G in the third position of the codon both correspond to leucine. If you look at 4 o’clock you’ll see that leucine also corresponds to CUa/c/g/u. So all these codons: UUA, UUG, CUA, CUC, CUG, CUU correspond to leucine.
So why the redundancy? Because in this way the genetic code is more tolerant to mutations. Say you’ve got an mRNA sequence containing UUA, meaning leucine. If there is a mutation that causes the last A to change into a G, then the amino acid is not changed - the mutation is silent. The final protein product is not altered and everything is fine. See, our bodies have these amazing mechanisms to protect themselves from harmful things!
Start and stop codons
Remember when I said there are 20 amino acids? Well I lied! Not entirely though. There are 20 amino acids which can be incorporated in a protein, but there is also a start codon and a stop codon.
The start codon is usually AUG and it tells the ribosomes that this is where they should bind to the mRNA and start workin’!
The stop codon can be either of UAA, UAG, UGA and when a ribosome reaches such a codon it stops its work and the detaches from the mRNA.
After the ribosome detaches the mRNA is either degraded, or is stored in certain places in the cell’s cytoplasm so it can be re-translated later.
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mRNA -> proteins (aka translation)
By Alex | July 5, 2008
This is the second step in the mechanism of building proteins and ultimately a new organ, or a new tissue. The key players in the process of translation are ribosomes.
What are ribosomes?
They are complexes made up of RNA (called ribosomal RNA, or rRNA) and over 50 proteins. This is their 3D structure (pic taken from here):
Free ribosomes are found in great numbers in the cell cytoplasm. When some translating needs to be done ribosomes attach to an mRNA molecule like so:
Picture taken from here.
The ribosomes read the nucleotides in the mRNA by groups of 3. Such groups are called codons. To each codon from the mRNA the ribosome allots an amino acid. All the amino acids for all the codons in the mRNA will form the protein.
Where do the ribosomes get the amino acids from? The tRNA story
Amino acids are found in the cell cytoplasm. They are brought to the ribosome by another special type of RNA, called transfer RNA (tRNA) which you can see in brown in the image above. The tRNA has one end which binds to the mRNA codon and another end which binds to the corresponding amino acid so there is one tRNA for each amino acid.
The tRNA enters in a hollow space in the ribosome, binds the codon and the ribosome “glues” the amino acid carried by the tRNA to the previous amino acid.
Then the ribosome shifts to the next codon on the mRNA, another tRNA brings the next amino acid and the process continues.
My next post will be on codons and amino acids. Stay tuned!
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Transcription factors
By Alex | June 6, 2008
So we’ve seen that DNA is transcribed into mRNA by an enzyme (a fancy protein) called the RNA polymerase. This is the first step in making proteins (the itty-bitty parts we’re all made of).
Now here’s a conundrum: our organs are made of cells - for ex. the liver cells are called hepatocytes, the lung cells are called pneumocytes, the brain cells are called neurons. And of course each of these cell types have different roles: hepatocytes filter all we ingest and metabolize it, neurons send off signals to our muscles (among other things), pneumocytes are key players in the gas exchange (O2 and CO2) with the hemoglobin in the blood.
As I’ve said before, the cell functioning is based on proteins - the proteins are the little wheels which interact with each other and set the cellular machinery in motion.
Obviously the cellular machineries are different between cell types, so all the little wheels (i.e the proteins) are different between liver and lung.
Now the question is: given that all our cells carry the same DNA in their nucleus, how come the proteins resulting from this DNA are different?
Well the thing is that not all cells express all their genes in their DNA - meaning that a certain gene is not transcribed into mRNA and then translated into protein in each and every cell, so the protein content of pneumocytes will be different from that of neurons. Thank goodness for that!
What determines what proteins will be produced in each cell?
Well, when a cell transcribes a gene into mRNA the polymerase can’t do the job by itself. It needs some help. That’s given by the transcription factors (TFs). These are also proteins which recognize a certain DNA sequence and bind to it, and can call the RNA polymerase: “Hey, polymerase, come here, I need you to transcribe this gene. Hurry up!”. So if in the vicinity of a gene (before or after the gene sequence) there is a sequence recognized by a TF, that gene will be transcribed.
Other TFs are not that sociable, and they suppress the RNA polymerase’s access to the DNA: “Step away from this gene, or I will shoot you” (well, not really shoot, they don’t have guns, doh!), and the gene will not be transcribed into mRNA => the corresponding protein will not be formed.
The image below shows a complicated example(found here):
- DNA is in purple
- the red key is a TF which fits (binds)into the key hole (the DNA sequence) ahead of a gene
- this leads to the activation of the transcription machinery (green choo-choo train) which creates a lot of mRNAs of the same gene (the blue curvy lines)
- these mRNAs can lead to proteins which are in fact many copies of another TF (little orange keys)
- these orange TFs bind to another DNA sequence, leading to transcription of another gene which can also encode a TF.
The key is that each cell has a certain set of TFs. The pneumocytes will have the TFs which bind to DNA sequences around genes necessary for gas exchange and they don’t have the TFs necessary for transmitting signals to muscles. So the pneumocytes will produce only a limited amount of proteins, necessary to their function, not all the proteins which are encoded by the entire DNA.
Some examples of TFs: Jun, Fos, Sp1 (don’t ask me how/why they were given these names). The image below (from here) shows how 3 TFs can interact and together lead to activated transcription.
Things are quite complex and scientists are only just beginning to understand the works of the matter.
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DNA -> RNA (aka transcription)
By Alex | June 2, 2008
How do we go from DNA to proteins?
This passage from DNA, i.e genes, to protein is called gene expression. Meaning that if a gene is expressed then the corresponding protein it encodes is created, and if the gene is not expressed, the protein is not formed.
There are 2 steps in gene expression: transcription and translation. First of all the gene is transcribed into messenger RNA and then the messenger RNA is translated into protein.
This post will just cover the first part: transcription - the passage from DNA to RNA.
First of all: what is RNA? RNA is the ribonucleic acid, and it’s a lot like DNA but it’s also a lot different. Let me explain the main differences:
- We’ve seen that DNA is double stranded. RNA is mostly single stranded (sometimes 2 strands of RNA can pair and form a double strand, but that is only temporary).
- As far as the base composition of RNA goes, it uracyl (U) instead of thymine (T) found in DNA. All the other bases are the same: A, C, G, U. When double stranded RNA does form, the U will pair with A and C will pair with G.Here’s an RNA molecule near a DNA molecule (from www.mcat45.com):
I mentioned above that DNA is transcribed into messenger RNA (mRNA). What is mRNA?
There are different kinds of RNA molecules: some store genetic information (like DNA does) and some of them have catalytic potential, meaning that they help chemical reactions to take place.
mRNA carries genetic information and can be seen as an intermediary between DNA and protein.
- How exactly is transcription done? How is mRNA created from DNA?
Transcription is based on the cell’s transcriptional machinery made up of a lot of different proteins, each with a very well-defined role. They are called enzymes = proteins that catalyze chemical reactions. For ex. one of the many proteins involved in transcription from DNA to mRNA is the RNA polymerase which reads one of the DNA strands base by base and creates the strand of RNA.
The newly-created mRNA is an exact copy of the DNA piece (gene) it was transcribed from, with the exception of Ts being replaced by Us.
The RNA polymerase reads one base at a time, but for this it has to have access to the base so the base pairs (A-T, G-C) have to be separated temporarily. This is not done for the entire DNA helix, just for a few bases at a time and just enough for the RNA polymerase to read the exposed bases. Then the bonds between the DNA bases are re-formed. We don’t want to destroy the DNA, now do we? ;). The enzyme that un-winds the DNA is called helicase (which comes from helix, get it?)
- Where do the A, C, G, U bases come from?
They come from the cell - each cell has the capacity to produce the 4 bases. It’s well equipped and can create the bases from scratch. SO the bases are floating away in the cell and when the polymerase needs them, it fetches them and assembles them into mRNA.
Here’s a picture I found here, explaining the main concepts:
- the big bubble is the RNA polymerase- the DNA is in blue: each strand in a different shade
- the newly formed mRNA is in red
- now, what does template mean in this context?
The template is the DNA strand used as a model to make the mRNA. Either one or the other strands are used as template, never both of them. And which one is chosen depends on many factors which I’ll discuss later.
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Proteins - the bricks of life
By Alex | May 29, 2008
Proteins: we have all heard about them. They’re the basis of all living organisms. All the little parts of each cell are made of proteins, and all the machinery that leads to a cell functioning properly is based on proteins interacting with each other.
What are proteins made of?
Proteins are compounds made of amino acids which are molecules made of carbon, oxygen, nitrogen, phosphorus and sometimes sulfur atoms.
You can think of an amino acid as a bead. If you put say 100 of these beads together you get a nice necklace. That’s the primary form of your protein in its infancy. Next the protein transforms, matures if you will. While doing this it folds and twists - imagine you’re crumpling the necklace in your hand. That’s how a protein looks like once it has matured. It’s no longer a simple string of beads, it has a more complex 3D structure. Check out this image:
Proteins interact with each other - a lot like LEGO pieces. Imagine that when you crumpled protein A, it has a bump on one side and protein B has a groove, a hollow space on one side. The bump of protein A can fit into the hollow space of protein B, and that’s how the wheels are set in motion!!! The interaction of A and B can make protein C change its 3D shape and interact with protein D, and so on and so on…
The above image is the result of a computer modeling of the interaction between 2 proteins. Pretty cool, huh?!
Examples of proteins:
Aldehyde dehydrogenase is a very important protein in alcohol metabolism, and is partly responsible for the next day hangover 
Myosin is a protein found in the muscle fibers.
Ferritin is involved in the iron metabolism in the liver.
How are proteins made? Or better yet: why don’t humans have green fluorescent skin?
Because we don’t produce the green fluorescent protein (GFP)! So it’s the proteins that our bodies produce that make our bodies the way we know them. There are proteins specific to humans that are not found in fish or in fruit flies.
GFP is actually a protein produced by the jellyfish and which has been widely used in science.
The array of proteins that an organism produces is dictated by their genes.
What’s the connection between proteins and genes?
Each gene encodes a different protein, so the fact that we don’t have green fluorescent skin is basically due to the fact that we, humans don’t have the gene which encodes the GFP.
So what about green mice?
Oh, you mean like these guys here?
They were genetically engineered (they’re called transgenic mice): the GFP gene was introduced into the mouse embryo. Then all the embryonic cells integrated the GFP gene into their own DNA. So when the mouse is born all its cells will produce GFP.
I’ll talk about why we use of transgenic mice in later posts.
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From DNA to genes
By Alex | May 28, 2008
Ah, DNA! It seems to be on everyone’s lips nowadays! DNA = deoxyribonucleic acid and it’s probably the single most important molecule that defines us as a species.
In human cells DNA is most of the time double-stranded: think of it as 2 chains that are twisted around each other. Each chain is made of different links called nucleotides (or bases): adenine, cytosine, guanine and thymine (A, C, G, T). The A on one chain has to pair with the T on the other chain, and the G on one chain pairs with the C on the 2nd chain.
So if we know the sequence of nucleotides on one strand, we can find out the sequence of nucleotides on the other strand. That’s because the 2 strands are complementary!
Here’s a picture illustrating this:
I’m sure everyone knew almost all of this, or at least the main concept of DNA. But do you know what’s the length of the human DNA? 3.2 billion base-pairs. That’s a lot!
Next item on the list: genes!
You probably know that genes are inherited (that’s partly correct, see later posts) from our parents. And they dictate how the human body develops and grows from birth till death. I won’t get into details right now, you’ll have to have a little patience!
Now the question is what’s the connection between DNA and genes?
That’s an easy one: genes are simply just pieces of our DNA and we have around 30,000 of them. Genes don’t have the same length - it can vary between several hundred kilo-bases (1kb = 1000 bases) to several mega bases (1Mb = 1 million bases).
Here’s something you probably didn’t know: the frog has around 30,000 genes as well. But you’d say that humans are “slightly” more developed and more complexly-built than froggies. Doesn’t the functioning of a more complex organism require more genes than that of a less complex one? Not necessarily.
It’s not the gene itself that counts for the functioning of an organism, it’s the product of the gene - protein/s (see later posts). In eukaryotes (living things other than bacteria) the same gene can lead to several different proteins. In more evolved species the same gene leads to more products compared to inferior species.
That’s why humans can write blogs and frogs can only say “ribet! ribet!”
Topics: Basic genetics | 1 Comment »
Why a blog on genetics?
By Alex | May 26, 2008
First of all welcome! And I accept your congratulations for this first post - you’re very kind!
Second, let me explain what’s in the sidebar pictures: well the one on the left is quite obvious. The one on the right is a picture from an in vitro fertilization procedure: the cell you see is an egg and the syringe carries the spermatozoid which will be inserted into the egg - a zygote is formed!
So why a blog on genetics?
Because of phrases like “[the super ability] is hard-coded into their DNA” (an episode of the TV show Heroes). This has absolutely NO PERTINENT MEANING! And personally I find that watching such a show is pretty much like watching Dumb and Dumber and I don’t understand why some would choose to witness such an awful display of wrongly-used concepts.
That’s why I’ve decided to share what I know on genetics topics such as chromosomes, gene expression, genes and disease, etc.
This is a great practice for me as well - it will help me to better present my ideas in a less-scientific language which always comes in handy when I have to tell D about what I’m doing in the lab.
So if you’re interested in reading a bit about what’s new in the world of molecular biology, stay tuned! I promise I’ll try to make it fun, not boring and easy to read. I’d love to hear your ideas/questions/comments, so if you have a theme in mind that you’d want to see on Genetics baby! just leave a comment.
See you soon!
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