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.