You are studying a family in which some members are affected

You are studying a family in which some members are affected with a rare serious disease. You have identified the gene responsible for the disease phenotype and then sequenced the gene in affected and unaffected individuals. Sequence from the same region of the unaffected and affected alleles are shown below. The partial sequences shown for each allele begin with the +1 base and represent sequence obtained downstream of +1.

Solution

The rare serious disease referred to here is a trinucleotide repeat disorder, also known as trinucleotide repeat expansion disorder. It is a mutation caused in the DNA of the coding region of a gene which already consists of a specific number of tandem repeats. During DNA replication, from the original tandem repeats, a trinucleotide set may loop out, leading to an erroneous increase in the number of trinucleotide repeats in the replicated DNA. This is also known as slippage leading to a dynamic mutation.

In the case being studied, the gene responsible for the phenotype of disease, in the unaffected individual in the family consist of 13 CGA trinucleotide repeats, which is lower than the threshold and is considered to be normal. Whereas, the individuals who are affected, this gene have more than 40 CGA repeats. Since CGA codes for the amino acid Arginine, such trinucleotide repeat expansion leads to disrupted protein function and the manifestation of severe diseases.

It is a form of genetic anticipation because repeat counts increase with every successive generation leading to increasing in severity and early onset of disease. More the number of repeats faster is the disease progression.

Molecular basis of trinucleotide repeat expansion disease

The number of trinucleotide or codon repeat in the gene, if remains within a certain threshold, is harmless or normal. If it crosses the threshold, then the disease associated with the mutant gene unfolds. The nucleotide expansion occurs in a multiple of three because such expansion does not cause frameshift mutation and does not hamper the expression of the gene. Since three nucleotide forms a codon for an amino acid, expansion of trinucleotide repeats results in the synthesis of a poly-amino acid tract.

For example, diseases like Fragile-X syndrome and Huntington disease are caused by trinucleotide repeat expansion.