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At a molecular level changes in the DNA sequence can cause an inherited disease, as simply put, the information coded for by DNA sequence corresponds to the sequence of the amino acids expressed during the processes of transcription and translation. This means that if there is mistake or mutation in the DNA, the wrong information would be expressed in the proteins, as possibly a non-functional protein which would be unable to complete its role in a metabolic pathway.

The central dogma of molecular biology

The central dogma of molecular biology is the name of mechanism which enables the information coded for by the DNA to be expressed into a range of biological molecules, which perform a variety of essential functions within the cell. It can be separated into three main steps; DNA replication, where information from DNA is transferred to another DNA molecule. Transcription, which is the movement of information from DNA to RNA and translation, the processes were the information stored in an RNA molecule, is translated into proteins.

There are more parts to the central dogma idea, however, they only occur under specific conditions, for example the movement of information from RNA to DNA. Which occurs during the replication of retroviruses due to use of a reverse transcriptase enzyme such as HIV-1 (Anon, 2010), inside a host cell  

Transcription

Mammalian Transcription starts with the binding of the Pol II RNA polymerase, alongside a transcription factor to a specific location on the DNA sequence called a promoter sequence, this produces an RNA polymerase-promoter complex, which undergoes a change in conformation that separates the DNA strands into two single stranded sections, referred to as the transcription bubble, this enables the RNA molecules to become associated with the template strand of the DNA, to start to produce an almost exact copy of the coding strand however using RNA nucleotides, moving in the 5’-3’ direction. This process can be referred to as initiation.

The next stage of transcription is called Elongation (Watson, 1987, page 429), in which the pre-mRNA molecule created by the polymerisation of the RNA nucleotides, in a reaction catalysed by the RNA polymerase, continues downstream the DNA (shown in fig 1) until a stop codon is reached, causing the termination step. In eukaryotes this step is still not completely understood (Lodish, 2016), however it has been found that a protein associates with the phosphorylated carboxyl-terminal domain (CTD) on the RNA polymerase Pol 11, this prevents the termination; until a set location downstream of the gene (Lodish, 2016) is transcribed into RNA.

Translation

The pre-mRNA is processes and turned into mRNA. This mRNA then leaves the nucleus through a nuclear pore into the cytosol where the large and small subunits of the ribosome assemble around the start codon located one the mRNA. This process creates the three binding sites located on the ribosomes for the tRNA to bind. The aminoacyl (A) site in which binds to incoming tRNA and the complementary codon of the mRNA. The peptidyl (P) site where the amino acid group attached to the end of the tRNA molecule comes into contact with the growing peptide chain. The exit site (E) in which the tRNA molecule after losing its amino acid exits the ribosome.

Mutations

Mutations in the DNA can occur spontaneously during DNA replication by a multitude of ways. With a common one being the mispairing of DNA nucleotides due to a rare alternate resonance structure of the nitrogenous bases, referred to as a tautomer; being able to interact and pair in a nonstandard way with another base which the ordinary form could not interact with, producing a tautomeric shift. As this style of mutation only produces a change in one of the bases located on the DNA it is a point mutation, with only one of the codons being affected. As DNA is a degenerate code, this kind of mutation has a chance of having no overall effect, as the new, mutated codon could code for the same amino acid as the wildtype codon. If this mutation occurs in one of the gametes cells it can lead to the offspring having the DNA mutation located though out all of their cells.

Another type of mutation that the DNA can undergo is a frameshift mutation, which most commonly created by an Indel mutation (short for insertion or deletion), these mutations are due to a base being added into the sequence, this would cause all of the bases downstream of the mutation to be shifted. This means that a string of ABC-DEF-GHI undergoing an insertion mutation (referred to as a plus) would turn into ABC-DXE-FGH-I, with the codons downstream coding for different proteins. The protein will be non-functional and can vary in size, as the stop codon which would make either the RNA-polymerase or the Ribosome detach from the DNA or mRNA strand respectively, will be distorted meaning that translation/transcription will continue until it encounters another stop codon. This kind of mutation produces a larger chance of a non-functional protein, due to the large change.

A missense mutation is where either an indel or frame shift mutation creates a stop codon prematurely, hence the protein translated from the missense mRNA will be truncated and normally non-functional.   

Sickle Cell Anaemia

An example of how a single point mutation can cause a disease would be sickle cell anaemia.

Haemoglobin is a globular metalloprotein, with the most abundant type of haemoglobin being HbA, which is made of two alpha chains and two beta peptide chains, with each one of these chains containing a heme group. In shorthand the main type of unaffected Haemoglobin is referred to as HbA and version with the mutated beta chain found in sickle cell anaemia chain as HbS

Sickle cell anaemia is caused by a single base chain on the gene coding for the beta chain for haemoglobin, from an A to T, this alters the codon from a GAG to GTG. This error is carried forward through the expression of the gene, and leads to the creation of a beta chain with valine (hydrophobic) in position 6 (Nature.com, 2018), with the wildtype having a glutamic acid (hydrophilic).

This mutation under normal conditions in benign yet during periods of low oxygen concentration (when the HbS is deoxygenated) it causes a shift in the conformation of the protein to expose a hydrophobic section, that would normally be covered in HbA. The hydrophobic R group located on the mutated valine can interact with producing the ability of multiple HbS to polymerize into large fibrous structures (Marie-Hélène Odièvre, 2018).  In people who are heterozygous for the HbS gene, these interactions do not cause serious problems as there should be equal amounts of HbS and HbA, as there is a reduced amount of HbS, making an HbS – HbS interaction rarer.

However, if the person in homozygous these interactions between the HbS create a large amount of fibrous build up in the red blood cells. Red blood cells are highly specialised to be flexible and malleable, so the polymerized HbS distorts the red blood cells into an elongated and solid shape, which cannot recover even when back into an oxygen-rich environment.

The main symptoms of sickle cell anaemia are due to the physical shape of the deformed red blood cells, for example Vaso-occlusive crisis occurs when the Sickle-shaped red blood cells become lodged in the capillaries and prevent blood from reaching important organs causing intense pain, organ damage and necrosis. With the main treatment being the transfusion of red blood cells from non-effected individuals, and in less serious occasions the use of NSAIDs (nonsteroidal anti-inflammatory drugs) (Olujohungbe, 2013).

An example of how the physical properties of the Sickle cells can create a positive feedback loop to cause a serious condition, is Acute chest syndrome. Where either an infection located in the lungs triggers an immune response, causing inflammation; or Vaso-occlusive causing cell death in the lungs. These cause a dramatic decrease in blood oxygen levels, this exacerbates the amount of HbS polymerization leading to a greater number of sickle-shaped cells. These conditions are the main cause of death for people with sickle cell (Damjanov, 2005).

Li-Fraumeni syndrome

A second disease that’s pathology is due to a mutation of a critical gene is Li-Fraumeni syndrome. Li-Fraumeni syndrome is a rare genetic disorder in which a tumour suppressor gene undergoes a mutation and becomes unfunctional or partially functional, this dramatically increases the risk of getting cancer. The two genes, which if undergo a mutation can cause the syndrome are the CHEK2 and the TP53 genes (TP53 gene, 2018), both of which are tumour suppressor genes. With the TP53 mutation being the most common cause of the Li-Fraumeni syndrome with some debate if mutations in CHEK2 gene cause Li-Fraumeni syndrome or simply an increased risk of cancer, similar to the symptoms of Li-Fraumeni syndrome (Genetics Home Reference, 2018).

The CHEK2 gene encodes for the checkpoint kinase two (CHK2), CHK2 has been observed to interact with the p53 protein which leads to cell cycle arrest in phase G1, as well as being a vital component in the DNA damage checkpoint system as it is activated when the DNA undergoes a double-strand break and prevents the cell to continue dividing. A mutation of the CHEK2 gene would lead a protein with a different conformation from wildtype CHK2 preventing it from being able to bind to the DNA and activate a pathway that would lead to cell cycle arrest, furthermore, a cell with DNA damage would be able to continue to replicate. The main mutation of the CHEK2 gene is a single deletion of a nucleotide at position in 1100 (referred to as 1100delC) leading to a frameshift mutation that produces a shorter non-functional protein.

The other main mutation that can cause Li-Fraumeni syndrome is a mutation in TP53, as the protein that it codes for a protein called p53, which has a variety of functions in the process of DNA cell repair. In normal conditions when the cell encounters mutagenic agents, that are known for causing double-strand DNA breakage, the TP53 gene is expressed alongside an enzyme called ATM protein kinase being activated. ATM protein kinase phosphorylates kinases proteins which leads to the post translational phosphorylation of the p53 protein. This phosphorylation of p53 stops the proteins from interacting with an enzyme called Mdm2; that would normally mark the p53 protein for destruction, this process is referred to as p53 stabilisation (Hardin and Bertoni, n.d.). After the stabilisation, the p53 binds to a specific sequence on the DNA and causes the activation or repression of its target genes, via the method of interacting with transcriptional factors.

As stabilization of the p53 inhibition of the destruction of p53 in damaged cells leads to the build-up of p53 in the cell. This causes the cell to undergo cell death or cell cycle arrest, depending on the amount of damage if the cell is able to repair the damage.  

The mutation of the TP53 gene is dominant, so it can be inherited; however, as the one of main symptoms is the early onset of cancer, most cases of the syndrome are due to either germline mutations or mutations early in embryogenesis. In 60-80% of Li-Fraumeni syndrome sufferers, there are detectable germline TP53 mutations, with the majority of these being missense mutations in the DNA binding domain of the protein (Malkin, 2011), normally in exons between 5-8. With the types of mutation being very similar to other of cancer, with less G:C to T:A transversions and more A:T to G:C transitions (Mutations in p53, p53 protein overexpression and breast cancer survival, 2009).

Since the mutation of the p53 is located in the DNA binding region, post p53 stabilising the p53 is unable to bind to the target DNA sequence, and change the gene expression. This leads to no prevention of the cell cycle of a damaged cell, hence enabling the cells to undergo uncontrolled growth leading to a much higher probability of cancers.

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