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Effects of Changes in DNA Base Sequences into Genetic Disorder Inheritance

Sickle Cell Anaemia
In 1910, sickle cell disease (SCD) was first noted in a dental student who was said to have pulmonary problems and was, and still is today, recognised by the characteristic ‘sickle-shaped’ erythrocytes, a term coined by Herrick after seeing the abnormal structures in his patient (Herrick, J.B, 1910). SCD is a broad term used to describe a myriad of genetic disorders that derive from a mutated form of the beta globin (HBB) gene. Normally, the HBB gene is responsible for the synthesis of beta globin, a subunit of a larger protein, haemoglobin, yet in sickle cell diseases, such as sickle cell anaemia (SCA), errors occur in the production of this polypeptide (Ballas et al 2012). A recent study had shown that in the UK alone, there are 14000 people living with SCA in the UK which is roughly the same as 1 in 4600 people (Dormandy, James, Insua and Rees 2018). Thus, with so many people suffering from such a horrific disease, we are brought to the question of what is SCA at a cellular level and how is it caused?
From base sequence to beta globin: the formation of SCA
Berg et al (2018) points out that there is a structural hierarchy that exists within cells. With respect to SCA, this is reinforced in so far as if any error occurs within the hierarchy at any given point, in this case, at the most basic and fundamental level at the DNA base sequence, this can have direct consequences on the conformation and structural properties of enzymes and proteins. SCA is the result of sickle haemoglobin synthesized as opposed to the predominant, healthy adult form. A point frame mutation occurs at the HBB gene located on chromosome 11 whereby adenine is replaced with thymine, resulting in the codon GTG as opposed to GAG. The consequence of this is that GTG, once translated, will lead to the synthesis of the amino acid valine as opposed to glutamic acid. Whilst this effect seems minimal, the result of this is that valine being a non-polar amino distorts the structure and folding of the polypeptide, resulting in hydrophobic interactions to form in the proteins tertiary structure, thus causing the sickle cell haemoglobin (HbS) to form (Ingram, 1956).
In contrast, in healthy haemoglobin that is composed of four polypeptide chains, two of which are alpha globin and the other two beta globin which form ?? pairs and share each an iron containing Heme group which enables the haemoglobin to associate and dissociate with oxygen in different partial pressures (Lukin, 2003).However as for sufferers of SCA, their ability to associate with oxygen is dramatically reduced. In fact, in deoxygenated conditions, strings of HbS are inclined to essentially adhere together which is facilitated by the fact that there is no nucleus in red blood cells, hence resulting in the typical biconcave shape of haemoglobin to be distorted so easily into the crescent like shape that characterises SCA (Berg et al, 2018). As of this, suffers of the disease often report to feel quickly out of breathe and experience chronic pain in regions whereby the HbS aggregates and leads to cell distortion, however, there are numerous treatments such as hydroxyurea seem hopeful in reducing such symptomologies (Charache et al, 1992).
The inheritance of SCA:
As SCA is a result of a mutation on the HBB gene, the trait can also be inherited in offspring since it is genetic. SCA is a recessive genetic conditioning, meaning individuals can either be heterozygous and thus a carrier or homozygous recessive, hence a sufferer. Thus, by the laws of monohybrid inheritance, If the parents of the offspring are both heterozygous or homozygous recessive, the chances of the offspring inheriting the disorder are increased (Neel,1949). It would be thought then that such a unfavourable genotype would be selected against by natural selection, however it seems as though the inheritance of SCA has a heterozygous benefit, particular for populations in Africa whereby the genotype is most frequent since individuals are still able to produce some healthy HbA whilst at the same time having a some form of resistance that the mutated HBB gene seems to confer (Nagel et al,1985). It was believed that by having the sickle cell genotype, this helped prevent the parasites ability to invade the host cell, however, recent research has proved this to be wrong. As opposed to preventing the invasion into the host cell, it appears “sickle haemoglobin makes the host tolerant to the parasite” as Miguel Soares quotes. Soares and his collages argue than the expression of the enzyme, heme oxgygenase-1 (HO-1) is strongly induced by sickle cell haemoglobin. It has been shown that this enzyme produces carbon monoxide gas previously in the lab, which now scientists believe confers protection to malaria. Soares and his team elaborate, stating that when carbon monoxide is produced in response to HbS seemed to have protective effects on the infected host cell from developing malaria, whilst at the same time, not affecting the parasites life cycle inside the erythrocytes. (EurekAlert,. 2018). Thus, having this heterozygous advantage means, unlike most genetic disorders, that the allelic frequency for sickle cell anaemia in the whole population will not be subject to selective removal, yet in fact, will even be selected for in places whereby malaria acts as a big selection pressure killing thousands such as in sub-Saharan Africa affecting up to 3% of births (Grosse, S.D et al, 2011)
Haemophilia – ‘The Royal disease’
SCA however is not the only genetic disorder that one can inherit, nor is monohybrid inheritance the only way we can inherit genetic disorders. Haemophilia, which means love (“philia”) of blood (“haemo”) seems to be an ironic name to give to the sex linked disordered, characterised by prolonged and excessive bleeding (Fijnvandraa, K. et al 2012). Haemophilia has been called a “royal disease” largely because the haemophilia gene was passed from Queen Victoria, who became Queen of England in 1837, to the ruling families of Russia, Spain, and German (, 2018). During the formation of a blood clot, precursor proteins such as factor VIII enter a cascade of enzymatic events to lead to the synthesis of Fibrin, a protein that enables blood clots to form to prevent excessive bleeding. However, it has been noted in recent years that there are polymorphisms in the factor VIII genes in sufferers of the disease (Bowen, DJ. 2012). Haemophilia can be separated into Haemophilia A and B which arise because of a different, yet similar, precursor protein gene involved in blood clot formation being mutated. Haemophilia A is four times more present in the population as opposed to Haemophilia B, with Haemophilia affecting 1 in 30,000 males whereas Haemophilia A affects 1 in 50,000 males (Lilicrap D, 1998).
The biochemistry of Haemophilia –
45% of cases being a result of inversion mutations, yet this does vary – for example, studies have reported numerous cases of substitution mutations also. Consequently, this changes the conformation of primary structure of factor VIII (Bowen, DJ. 2012). Recent molecular studies have shown that in at least five Haemophilic patients, a A>G mutation changes AAT to GAT, and in turn neutral amino acid asparagine becomes negatively charged aspartic acid. This can therefore disrupt the non-covalent e.g. ionic bonding between R groups in the proteins tertiary structure, thus leading to a non-functional form of factor VIII in its A2 domain. Due to this deficient protein, Haemophiliacs have a lack of Fibrin that circulates their body, thus, even a simple bump on the head can cause bleeding into the brain for some people who have severe haemophilia (Owaidah, TM et al. 2009).
The inheritance of Haemophilia:
Any gene that is found either on the X or Y chromosome is said to be sex linked. However, the X chromosome is much longer than the Y chromosome, meaning that for most of the length of the X chromosome, there is no equivalent homologous portion on the Y chromosome. Thus, characteristics that are controlled by recessive alleles on this non-homologous portion of the X chromosome, such as haemophilia will appear more frequently in the male, whose genotype is XY – thus, any recessive sex-linked disorder means that males will always be most affected as they cannot be heterozygous unlike women, hence why haemophilia occurs in about 1 of every 5,000. However, this is not exclusive to just men, as if a female was to inherit a homozygous recessive genotype, she too could be a sufferer, or yet, a carrier if she was to have the heterozygous genotype. However, haemophilic females is often rare since they are subject to death with the onset of menstruation at puberty (Centres for Disease Control and Prevention, 2018). As expected, this has resulted in the selective removal of this gene by the population, making its occurrence relatively rare, affecting about one person in 20,000 in Europe alone. (Centres for Disease Control and Prevention, 2018). Thus, if a carrier female and a normal male were to produce offspring, there would be a 50% chance that they could have male or female offspring who are not affected. However, there would then be a 25% chance that they could produce a carrier female and also a 25% chance they could produce a 25% haemophilic male.
Herrick J.B. Peculiar elongated and sickle-shaped red blood corpuscules in a case of severe anemia. Arch. Int. Med. 1910;6:517–52
Ballas, S.K., Gupta, K. and Adams-Graves, P., 2012. Sickle cell pain: a critical reappraisal. Blood, pp.blood-2012
Dormandy, E., James, J., Inusa, B. and Rees, D., 2017. How many people have sickle cell disease in the UK?. Journal of Public Health
Berg, J., Tymoczko, J. and Stryer, L. (2018). Biochemistry. [online] Available at: [Accessed 22 Oct. 2018].
Ingram, V.M., 1956. A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature, 178(4537), p.792.
Lukin, J.A., Kontaxis, G., Simplaceanu, V., Yuan, Y., Bax, A. and Ho, C., 2003. Quaternary structure of hemoglobin in solution. Proceedings of the National Academy of Sciences, 100(2), pp.517-520.
Berg, J., Tymoczko, J. and Stryer, L. (2018). Biochemistry. [online] Available at: [Accessed 22 Oct. 2018].
Charache, S., Dover, G.J., Moore, R.D., Eckert, S., Ballas, S.K., Koshy, M., Milner, P.F., Orringer, E.P., Phillips, G.J. and Platt, O.S., 1992. Hydroxyurea: effects on hemoglobin F production in patients with sickle cell anemia [see comments]. Blood, 79(10), pp.2555-2565.
Neel, J.V., 1949. The inheritance of sickle cell anemia. Science, 110(2846), pp.64-66.
Nagel, R.L., Fabry, M.E., Pagnier, J., Zohoun, I., Wajcman, H., Baudin, V. and Labie, D., 1985. Hematologically and genetically distinct forms of sickle cell anemia in Africa: the Senegal type and the Benin type. New England Journal of Medicine, 312(14), pp.880-884.
EurekAlert!. (2018). Mystery solved: How sickle hemoglobin protects against malaria. [online] Available at: [Accessed 24 Oct. 2018].
Grosse, S. D., Odame, I., Atrash, H. K., Amendah, D. D., Piel, F. B.,

Staphylococcus Genus Report: History and Treatment

Staphylococcus has the potential to be an extremely life-threatening bacterium. Some people have heard of it, especially certain strains or nicknames, but not many people know about the actual bacterium itself. Staph is an opportunistic pathogen (Fair), innocent until given the chance to invade a weak immune system or wound. Because of its effect on weak immunocompetent people, it happens to be the most common hospital acquired infection to date (Mayo Clinic Staff). Some strains are extremely contagious and others are not. Overall, Staphylococcus is a unique and interesting bacterium with over 40 different species. Of those, nine species have different subspecies, totaling 25 total subspecies.
In 1880, the Scottish surgeon Sir Alexander Ogston was the first person to identify Staphylococcus. He named it after the grape–like clusters he saw under the microscope from Greek origin, “staphyle” literally translates to “clusters of grapes” (Ordent par 2 and Licitra par 1). Ogston identified staph as a cause of post-operative wound infections. Later, in 1884, the first two species were isolated, thanks to Anton Rosenbach, a German scientist. He successfully isolated, in pure cultures, Staphylococcus aureus (S. aureus), and Staphylococcus albus (S. albus) (Ordent par 3). Later on, S. albus was renamed to S. epidermidis. Both of these two species are the most prominent and most studied (Parker et al. 159). S. epidermidis is generally nonpathogenic in humans, unless you have a compromised immune system. S. aureus can produce coagulase and toxins responsible for local and generalized infections (Parker et al. 180). A major and deadly strain of S. aureus is methicillin-resistant Staphylococcus aureus, or MRSA for short. MRSA is extremely resistant to almost all penicillin-related antibiotics and keeps evolving and learning, rightfully earning its nickname “the superbug”.
Staphylococci are spherical bacteria that form grape-like clusters because they can divide in two different planes rather than one chain (Microbiologists at Kenyon College). Although they have a coccus shape, they belong to the class Bacilli (Parker et al. 179). This bacterium is gram-positive and immobile. Staph is a facultative anaerobe, meaning it grows best under anaerobic conditions, but can survive, grow, and thrive in the presence of oxygen if necessary. These little bacteria love temperatures between 6-48°C, but grows best at human temperature, 37°C, making it a mesophile (Parker et al. 159 and Fair). However, certain species can completely survive freezing temperatures, like S. aureus, and recently, an extremely heat resistant form of S. aureus was found in India (Food standards). Their preferred pH is anywhere between 6-7, making them neutrophiles. Staphylococcus can also tolerate high salt concentrations and can grow on mannitol salt agar plates, or MSA plates for short (Parker et al. 180). In addition, Staphylococcus epidermidis uses dead human skin cells as nutrients to help survive and thrive (Parker et al. 151). This bacterium is extremely remarkable in its ability to be highly adaptable, adjusting to its physical environment, but also to antibiotics.
You can find Staphylococcus in several places both on the body and in your environment. Each strain can be found in different places. Humans are the main carrier of all staph bacteria and can easily pass it on to others. Almost all species of Staphylococcus are found on the skin (Parker et al. 916). On the body, S. aureus is commonly found on the skin and in the nasal and oral cavity. According to the CDC, at least 25% of the entire population carries S. aureus on their body (CDC). It can live inside both humans and animals (i.e., cows, dogs, poultry, etc.). S. aureus is also found on common surfaces like food processing areas and air ducts. Sometimes you can even find it on raw or frozen food. Certain Staphylococcus bacteria can survive being frozen, but none can survive heat. However, their toxins can survive heat and cause illness even after being cooked. S. epidermidis and S. hominis are prevalent on the skin as well. You will typically find S. epidermis in infectious skin wounds, prostheses, and most commonly in intravenous catheters.
Pathology and treatment
Staph infections can range from mild to life-threatening. Usually, a staph infection is only on the skin. To determine if a patient has a staph infection of their skin, the doctor will closely examine the skin lesion(s) (if applicable) and then run a series of tests to determine the strain behind the infection. A staph skin infection on the outside can be a pimple, boil, cellulitis, impetigo, folliculitis, or even an abscess. Sometimes this is caused by S. aureus’s production of coagulase. This is a plasma-clotting protein that is involved in abscess formation (Parker et al. 916). The remedy is a simple treatment of draining the abscess, boil, or pimple or an antibiotic topical cream to treat the rashes (Parker et al. 918). Identification and treatment are extremely important to prevent the infection from spreading and can prevent more serious issues from arising. A more serious skin infection caused usually by S. aureus is called staphylococcal scalded skin syndrome, abbreviated SSSS. Bacterial exotoxins produce erythema and then severe peeling of the skin. This condition is diagnosed by looking at the characteristics of the skin, blood tests, and cultures. Treatment includes intravenous antibiotics and fluid therapy (Parker et al. 918).
Even though a majority of staph infections are only on the skin, sometimes they go much further. Bacterial staph infections can also cause acute purulent conjunctivitis, acute ulcerative blepharitis, dacryocystitis, septic arthritis, blood poisoning (septicemia), urinary tract infections, and infections of implants, prosthesis, and catheters. S. epidermidis is usually completely harmless until it bypasses the skin through medical devices such as implants, prosthesis, catheters, and indwelling medical devices. Once inside the body, infections become hard to treat (Parker et al. 920). Treatment for this would be removal of the foreign object, sterilization and antibiotics. Septic arthritis, also called infectious arthritis, is most commonly caused by S. aureus and their bacterial pathogens cause inflammation in the joint tissues (Parker et al. 1114). This sometimes happens by an infection spread through the bloodstream to the joints, puncture wounds, drug injections, or surgery near the joint. Treatment includes draining the joint entirely by needle or with surgery, followed by antibiotics (Mayo Clinic Staff).
An important thing to note is that certain Staphylococcal strains, especially S. aureus strains, produce enterotoxins, chemicals, and certain toxins (Parker et al. 179). These bacterial toxins can cause several serious conditions in addition like Toxic Shock Syndrome, food poisoning, and pneumonia (Parker et al. 179 and Mayo Clinic Staff). Toxic Shock Syndrome (TSS) can be caused in many ways. Some strains of S. aureus produce a superantigen called toxic shock syndrome toxin-1, or TSST-1 for short (Parker et al. 1112). A diagnosis is made through clinical signs and symptoms, along with several tests (for example-vaginal swabs from a woman) to determine the bacterial species and their toxin production (Parker et al. 1112). Treatment for TSS includes decontamination, vasopressors (to increase blood pressure), debridement, and antibiotic therapy dependent on the strain’s resistance (Parker et al. 1112). S. aureus is also notorious for causing food poisoning; also called Staphyloenterotoxaemia (when the bacteria’s toxins cause inflammation and infection in the lining of the patient’s intestinal tract). There are at least twenty-one known Staphylococcal enterotoxins and Staphylococcal enterotoxin-like toxins that can cause food intoxication (Parker et al. 1060). If someone happens to ingest Staphylococcus (usually S. aureus) through contaminated food, they may cause symptoms like stomach cramps, nausea, vomiting, diarrhea, sweating, headaches, dehydration and fever and is treated with fluids and antinausea medicines (Parker et al. 1059). It is detected through stool or vomit samples, but for treatment, no antibiotic would be given here because antibiotics do not affect these toxins (CDC par 3 and Parker et al. 1060). It usually passes within a day or two on its own. Treatments of staph varies from species to species and where the infection is located (skin, bloodstream, joints, etc.).
The early antibiotic treatment of staph (the 1940-1950s) was penicillin. Due to overuse and abuse, a majority of strains are now penicillin resistant. As a result, only 10% of staph infections can be treated with penicillin (Mayo Clinic Staff). Only a few antibiotics are used today for treatment of staph, such as nafcillin (penicillin family), sulfa drugs and certain cephalosporins. The strain you have determines the antibiotic you receive. On the other hand, MRSA is completely resistant to a certain group of penicillin-like antibiotics called beta-lactams (Parker et al. 638). MRSA infections cause pneumonia, septicemia, and if left untreated, sepsis (CDC). In MRSA infections, the most common antibiotic used is vancomycin; however, there have been cases of vancomycin-resistant S. aureus. This new strain is nicknamed VRSA. Both MRSA and VRSA exhibit resistance to nearly every available antibiotic on the market, making it the most difficult to treat and the most lethal. The best way to prevent any staph infection is by practicing good hygiene such as good hand washing skills, sanitary food preparations, and keeping all wounds clean.
Good hygiene is important to prevent a staph infection, but it is also important not to be too clean. The body naturally carries bacteria on it. Some bacteria produce proteins that kill off other bacteria. An example of this is on the human body: the bacterium Lucilia sericata produces a protein that destroys Staphylococcus aureus. If you wash your hands too much, use too much hand sanitizer, or shower too often, you are at risk for getting a S. aureus infection or transmission (Parker et al. 151). This is why we normally see people who suffer from obsessive-compulsive disorder with frequent illnesses.
All species of staph are known as opportunistic pathogens, so they do not cause harm unless you have a weakened immune system (Fair). Some studies have shown that by having staph in your nose and mouth, it helps fight off other infections. Similar to the gut bacteria in the large intestine, they are not necessarily supposed to be there, but they are helpful. This bacterium is commonly used in labs for studying, learning, and testing new antibiotics and treatments. Furthermore, we are just know learning that S. epidermidis helps to balance out the microflora on your skin and serves as a reservoir of resistance genes (Otto par 1). Many scientists believe that in the beginning S. epidermidis had a non-infectious lifestyle (Otto par 2). It has even been proposed that S. epidermidis may have a probiotic function that prevents the colonization of more pathogenic bacteria, like its cousin S.aureus. But there is no solid evidence to support that yet (Otto par 5).
Staphylococcus is a highly adaptable bacterium that never stops learning. All forms of Staphylococcus can generate some crazy effects on the human body, but not all of them are bad. To think that you usually carry it on your body on a normal daily basis is even crazier. It is important to remember that maintaining good hygiene can play a tremendous role in the prevention and spread of this bacteria. By possibly controlling our hygiene we can start to curb the outbreaks of Staphylococcus and even MRSA in our communities.
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