The Second Coming
Did you come here anticipating a poetry evaluation of the poem whose title matches that of my article?
Don't be disappointed, though. I picked this title because I see some similarities between the context of my paper and the poet's (W.B. Yeats) point of view. Not in a literal sense, but, of course, in a scientific sense.
"Those who cannot remember the past are condemned to repeat it."- George Santayana
Have you ever gotten hooked on a single sentence when reading something? ...like reading the same phrase over and over because your brain mixes the beginning of one line with the beginning of the next. Of course, who hasn't?
What happens if, upon reading the DNA sequence, the enzymes also become confused?
Consider DNA polymerase repeatedly reading the template's DNA sequence. Then, what would happen?
You will now respond by saying that the freshly synthesized strand will have many copies of the same sequence. However, wouldn't that imply that the new strand and the template are incompatible? Should that be the case, will cells ever encounter this kind of context?
WHAT MAKES THE DNA POLYMERASE CONFUSED?
Replication slippage, or slip strand mispairing, is a captivating phenomenon observed during DNA replication.Â
Within our genetic blueprint, about 30% comprises satellite regions, characterized by repetitive sequences. These regions pose a unique challenge during replication, as they can induce mispairing between the coding and template strands. This mismatch occurs when the repeating sequence aligns improperly with a complementary sequence upstream, leading to the formation of intricate secondary structures like hairpins or stem-loops.
Despite the cell's sophisticated DNA repair mechanisms, which typically correct such errors, certain factors can sustain these secondary structures. These factors may include interactions with specific proteins, hydrogen bonding, or other molecular interactions. This highlights the dynamic interplay between DNA replication, repair processes, and the maintenance of genomic integrity, particularly in the face of repetitive DNA sequences.
This mutation can persist in the absence of repair processes. The majority of documented instances occur when Ku subunits of the NHEJ Complex are altered, there is a lack of nucleotide excision repair, or in response to oxidative glycosylation.
HOW DOES DNA POLYMERASE REACT TO SUCH A MUTATION?
When DNA polymerase encounters a direct repetition, the polymerase complex separates from the template and stops the replication activity. The newly synthesized strand then breaks from the template strand to align with another direct repeat upstream. The reassembling of DNA polymerase occurs on the template strand. This leads the polymerase unit to backtrack and insert previously added deoxyribonucleotides. As a result, the new strand has some repetitive sequences.
To resolve the issue, excision repair proteins are allocated to the template strand. To avoid a mismatch, they usually stretch the template strand. DNA contraction can also occur, however, DNA repeat expansion is the more common way.
Dinucleotide and trinucleotide expansions can occur; trinucleotide expansions are more prevalent.
WHAT ARE THE CONSEQUENCES OF THESE TRINUCLEOTIDE EXPANSIONS?
In most cases, trinucleotide extensions cause genetic disorders related to neuromuscular disorders and neurodegenerative diseases. Trinucleotide extensions near the gene sequences increase the risk of disease. Trinucleotides are easy to transcribe but are rarely translated. In rare cases, when they are transcribed, such repeat expansion reduces the function of the protein.It has been found that RNA produced from these repetitions can cause RNA toxicity in the body as found in Myotonic dystrophy. They are mostly trans-acting and can regulate the expression of other genes or simply make hazardous proteins.
According to studies, neuromuscular degeneration is connected with either a CGG or CAG repeat expansion. However, CTG repetitions are identified in certain situations. The length of this trinucleotide expansion area is usually what causes illness to start. There is no such thing as a universal length that can anticipate what will happen with any sickness. However, in some disorders, it has been identified. For example, in Huntington disease, the trinucleotide number is frequently greater than twenty, but in Fragile X syndrome, it may exceed 200.These enlarged repeats can be locations for significant epigenetic alterations that influence disease manifestation.Â
In some diseases, such as Huntington's disease, where a single gene mutation occurs, the trinucleotide repeat length determines the age at which the disease can manifest. Even a single trinucleotide expansion can result in a five-year rise in onset age. In some cases, such as Fragile X syndrome, the repetition length can predict the severity of the condition. Somatic expansions of these trinucleotide repeats persist throughout life. Expansions in germ cells determine transmission to the generations that follow .Â
Aside from the disorders stated above, I'll name a few others. Spinocerebellar ataxias include Friedrich's ataxia, Kennedy's disease, and Machado-Joseph disease, among others.Â
A GLIMPSE THROUGH THE MEMORY LANE;
Trinucleotide expansions were identified in the early 1800s as a possible cause of illness development, but many people dismissed the theory. The most noteworthy ones are the discovery of Fragile X syndrome and Huntington's disease.
Fragile X syndrome was the first illness to be discovered that exhibited such symptoms. Martin Bell discovered strange X-shaped chromosomes (constricted at the ends) in a sample of mentally retarded people and coined the term "Bell syndrome."
The characterization of Huntington's disease came next. The scientist was just 21 years old when he made the discovery. He found such expansion in the exon 1 of chromosome 4 of a single gene coding for huntingtin protein, in . Prior to this, some research was conducted on myotonic dystrophy and SMBA illness. The field certainly is growing over the past years in the directions of finding therapeutics, understanding the mechanisms of action etc. However challenges mostly lie in building models, collection of large disease samples for study and experiments, higher costs of treatment and limitations in the available technology.
SOME POINTS TO PONDER…
I much appreciate your patience in reading thus far into the text. But before signing out, I'd want to allow the reader to ponder about the following questions:
Why do the majority of trinucleotide repeat expansions involve the C and G bases?
Can DNA continue to expand indefinitely across generations if secondary structures stabilize? What determines the length of DNA in a species?
What is the possible inheritance pattern for these expansions?Â
Now to summarize, trinucleotide repeat expansion diseases are a set of complicated genetic illnesses that can have a significant impact on afflicted individuals and families. From Huntington's disease to fragile X syndrome, these illnesses cause a wide range of symptoms in the neurological, muscular, and other physiological systems. Understanding the processes that drive repetition expansion and the phenomena of anticipation is critical for both diagnosis and potential therapeutic approaches. As science progresses, there is hope for better therapies and, eventually, prevention of these terrible diseases. However, more research into the genetic and molecular complexity of trinucleotide repeat expansion syndromes is required to understand their full complexities and pave the way for future advances in clinical treatment and care.
REFERENCEÂ
1.https://en.m.wikipedia.org/wiki/Slipped_strand_mispairing
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