Putting A Magnifying Glass Under Genomics
And how Sherlock Solves his Mysteries
Elon Musk has died. So, Sherlock has a new case. The presumably invincible man had his cybertruck windows cracked and was murdered just before releasing the Tesla Model XYZ. BMW CEO Harald Kruger, Mark Zuckerburg, CEO of Facebook and Takahiro Hachigo, Honda CEO, are all prime suspects.
Luckily the murderer left the weapon, a flamethrower, on the scene. Now, we can compare the DNA to our suspects and bring justice. But how? I thought all DNA was 99% similar. Let’s take a step back.
The Building Blocks of Life: DNA
Deoxyribonucleic acid is well known for the four chemicals that make it up:
A — Adenine
C — Cytosine
T — Thymine
G — Guanine
The four letters are arranged in a specific sequence that makes up you and me. Two letters will pair to form a nucleobase by a non-covalent bond (not held tightly together), where A pairs with T and G pairs with C.
Think of these bonded letters as steps in a ladder. The sides of the ladder are sugar (ribose) and phosphate covalent bonds (it’s going to be hard to break those lovers apart). Sugar + Phosphate + Letter(base) = Nucleotide
If you split the ladder in half and wind up both pieces into a double helix…you got DNA. The two sides of DNA run in opposite directions. There are 6 BILLION nucleobases in a single cell🤯.
This DNA is held in chromosomes. To condense a HUGE amount of DNA, a protein called histone helps tightly wind the DNA until it forms one of the 23 types of chromosomes in your body.
But how does complex me function from some letters?
Within your genome(all your DNA) there are genes made up of a certain sequence of nucleotides with a certain length. These genes control different things: hair colour (MC1R), help your body replicate DNA, make blood cells, build the cell wall and influence what diseases you may have.
Genes help make proteins, which carry out the above tasks, histone is one you have already met. How proteins fold will determine their function.
In your cell, the endoplasmic reticulum helps produce proteins. The nucleus helps run the whole operation and the powerhouse, mitochondria gives the cell the energy it needs.
Making Proteins: Central Dogma
Your body has to get the DNA code from inside the nucleus to the endoplasmic reticulum(we will call it endo from now on) where it can make proteins from amino acids.
Chromosomes are too large to leave the cell so that's not an option. You may think there is a protein that brings the desired piece of DNA to the endo and it starts making proteins, but you would soon lose all your DNA.
Instead, imagine you’re trying to decipher a secret message. You have one minute to look at the cheat sheet showing what every letter actually represents. Then you have the rest of the time to crack the code on the other page.
1. Transcription — DNA Makes RNA
In the example above, your best to spend the first minute copying down the cheat sheet, and that’s exactly what we do.
Each gene in the DNA has base pairs representing a promoter and terminator region (beginning and end), signalling where the DNA should be copied.
Next, DNA Polymerase will start to form mRNA (messenger RNA). RNA is different than DNA in a few ways:
- It’s smaller than DNA so it can easily exit the nucleus
- RNA only contains one side of DNA
- G pairs with C, but A now pairs with U (uracil)
DNA Polymerase will start making pairs at the promoter region with one side of the DNA, following the pairs A — U and G — C. After forming all the pairs, the weak non-covalent bonds holding together the one side of DNA, and that created by DNA polymerase will split up and the copied sequence is mRNA, ready to leave the nucleus.
2. Translation
The next task is to break down the DNA code so we can use it to make amino acids (which then make proteins). The molecule, ribosome, does just that. Its large and sub-unit bind to the mRNA creating a sandwich, allowing it to crack the base code to make amino acids. Here’s the catch…
How can 4 base letters, make 21 different types of amino acids? Codons. Instead of reading the RNA letter by letter, it’s read in pairs of three, where each unique sequence codes for a different amino acid.
Ribosomes understand RNA through tRNA (transfer RNA). tRNA is like a computer charger, one end contains the amino acid or electricity in this example. And the other contains a codon, looking for the exact pair (anticodon). You can’t plug a Windows charger into an Apple computer because they don’t match. If it is a match the amino acid will be made.
A string of amino acids will form proteins, and depending on their shape and how they're folded, they perform certain helpful functions.
Now that you understand the basics of DNA, it’s time to crack the case!🔎
Telling the Difference Between DNA
Given that all our DNA is extremely similar, we can’t use the letters to tell the difference between suspects. Instead, we use the spaces in our DNA, now known as variable tangent repeats(VTRs). Through research, we learned each of us has certain amounts of a specific sequence of DNA that is constantly repeated throughout our genome. This is our real DNA fingerprint.
The repeated sequence will vary in length from person to person, some may have 50 base pairs repeated while others have 2. And the number of times the sequence is repeated can also vary from person to person. We can use these variations to convict the murderer.
PCR: Polymerase Chain Reaction
This invention proved huge for genomics. Without it, the human genome project, drug testing and crime scene investigations would not exist. PCR simply makes copies of DNA outside of the human body.
We first make a solution using the reagents which are mixed in a specific order, and placed in a test tube:
- Water
- Buffer (salt+other chemicals to help the reaction)
- Template DNA (the DNA we are studying: found on the scene)
- 2 Primers (one for each side of DNA)
- Taq DNA Polymerase (What will be doing the coping: think of DNA Polymerase)
- Nucleotides (we need them to make new DNA by attaching bases)
Now, the test tube is placed in a thermocycler, which is preprogrammed for a certain amount of repetitions. Each repetition includes three steps:
- Heat up the DNA to 95°C which causes the template DNA to unzip into two strands by breaking the weak non-covalent bonds
- Cooled down to 68°C allows the two primers to set on each strand of DNA *the primer bases must match the strand to set
- Heated to 72°C, the Taq DNA creates the appropriate base pairs which match the strand of DNA and attaches the nucleotides to fully copy the DNA
Gel Electrophoresis
With copies of all the DNA, we want to represent the spaces in the DNA visually. We use agarose gel which has holes within the gel. If someone's DNA has long VTRs, then it will take longer to move through the gel. So, we place all the suspect's DNA and the crime scene DNA in a race, each with its own lanes. All we need is a reason for the DNA to move through the gel.
DNA is negatively charged, so we can set a positive charge at the end of the race track since opposite charges attract. Now it’s time to look at the results!
I guess Elon was getting too much attention. We just scratched the surface of genomics. How about making oranges smell like bananas? Curing cancer with CRISPR? Predicting your chance of getting a disease with SNPs? Bringing back the dodo bird? The technology is out there, you just need to think big!
Key Takeaways:
- Our DNA is made up of nucleobases: ACTG along with phosphate and sugar
- Certain sequences of DNA are known as genes which code for amino acids that make proteins: the essence of how our body functions
- Transcription and Translation is how DNA is understood to make proteins
- PCR is a way of duplicating DNA outside of the human body
- On crime scenes, we look at spaces in our DNA, not the base letters to convict the offender
- The possibilities of genomics are only limited to the most ambitious
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