Question

Some mutations that lead to diseases such as Huntington disease are caused by the insertion of trinucleotide repeats. Describe how the process of DNA replication could lead to expansions of trinucleotide repeat regions.

Short answer

Short Answer: Trinucleotide repeats, sequences of three nucleotides repeated in tandem within DNA, can cause genetic disorders like Huntington's disease when their number exceeds a certain threshold. The expansion of these repeat sequences occurs due to errors in DNA replication, primarily from the formation of secondary structures (hairpin loops) in the template strand of the repeat region. These structures can lead to misalignment of the newly synthesized strand, resulting in the addition of extra repeat units. Over time and multiple rounds of replication, these expansions accumulate within cells, leading to the progression of the disease phenotype.

Step-by-step solution

Introduction to Trinucleotide Repeats and Disease

Trinucleotide repeats are sequences of three nucleotides repeated in tandem within a region of DNA. In normal individuals, these repeats are usually stable and have no harmful effects. However, when the number of repeats exceeds a certain threshold, they may cause genetic disorders like Huntington's disease. The expansion of these repeat sequences is responsible for the development and progression of such diseases.

DNA Replication Process

DNA replication is a fundamental process in cell division where a DNA molecule is copied to produce two identical DNA molecules. It occurs in a semi-conservative manner, meaning that each of the two resulting DNA molecules has one old strand (template) and one newly synthesized strand. The process has three main stages: initiation, elongation, and termination. During initiation, proteins unwind the double-stranded DNA and form a replication fork. In the elongation phase, DNA polymerase adds nucleotides to the newly synthesized strand by following the base-pairing rules (A pairs with T and C pairs with G). Termination occurs when the replication process is completed.

Expansion of Trinucleotide Repeats during DNA Replication

During DNA replication, the expansion of trinucleotide repeat regions can occur due to errors in the replication process. These errors can be caused by the formation of secondary structures (hairpin loops) in the template strand of the repeat region. The newly synthesized strand, which is complementary to the template strand, can mis-align itself with the template strand, pairing incorrectly with the repeat sequence. This misalignment results in the addition of extra repeat units onto the newly synthesized strand while the template strand remains unchanged. Next, during cell division, the daughter cells receive a copy of the DNA molecule containing the expanded trinucleotide repeat region. Over time and multiple rounds of replication, these expansions can accumulate within the population of cells, resulting in the progression of the disease phenotype. So, the process of DNA replication and errors occurring in it can eventually lead to expansions of the trinucleotide repeat regions responsible for diseases like Huntington's disease.

Key concepts

DNA Replication

The process of DNA replication is essential for cell division. It ensures that each new cell receives an exact copy of the DNA. The process occurs in a semi-conservative manner. This means that each newly formed DNA molecule contains one strand from the original molecule and one new strand. Let's break down how it works.

• Initiation: The double-stranded DNA unwinds with the help of special proteins. This creates a Y-shaped structure known as the replication fork.
• Elongation: Here, the enzyme DNA polymerase plays a key role. It adds nucleotides to form the new strand. It follows the base-pairing rules, where Adenine (A) pairs with Thymine (T), and Cytosine (C) pairs with Guanine (G).
• Termination: This is when the replication process is complete. The DNA strands rewind into their double-helix form.

During this meticulous process, mistakes can sometimes occur. These mistakes can lead to errors like the expansion of trinucleotide repeats in specific regions of DNA. Such errors often happen when the new strand misaligns, particularly in repetitive sections of the DNA.

Genetic Disorders

Genetic disorders arise due to abnormalities in the DNA sequence. These disorders can result from various factors, including the expansion of trinucleotide repeats. Normally, our DNA includes various repeating sequences that are stable. However, when these repeat regions expand beyond a normal threshold, they can become problematic.

Some genetic disorders linked to repeat expansions are inherited conditions. Often, they show distinctive inheritance patterns and can significantly impact an individual's health and development. Let's explore some impacts:

• Unstable Repeats: When repeats expand, they become unstable. This instability can lead to interruptions in gene function, causing diseases.
• Progression Over Time: With each cell division, longer repeats can cause the disorder to worsen over generations.
• Examples: Huntington's Disease is a primary example of a disorder caused by repeat expansion.

These expansions are integral to understanding various genetic disorders and their impacts on health. They emphasize the delicate balance and precision required in DNA processes.

Huntington's Disease

Huntington's disease (HD) is a well-known genetic disorder caused by trinucleotide repeat expansions. Specifically, it occurs due to the expansion of CAG repeats in the huntingtin gene. Normal individuals have between 10-35 of these CAG repeats, but in HD, this number can expand significantly, leading to disease development.

Understanding how HD manifests can help in grasping its challenges. Here are some key aspects:

• Symptoms: Huntington's disease is characterized by movement disorders, cognitive decline, and psychiatric issues.
• Inheritance: It is an autosomal dominant disorder, meaning a person only needs one copy of the mutated gene to develop the disease.
• Progressive Nature: Symptoms typically appear in middle adulthood, but they progressively worsen, affecting the individual’s quality of life.

Unfortunately, there is currently no cure for Huntington's disease, but understanding the role of trinucleotide repeat expansions can inform research aimed at possible treatments and interventions.