A doubt related to genetic mutations

[zahra02]

Hi! I'm a student currently trying to do the ScienceBuddies Project "From Genes to Genetic Diseases: What Kinds of Mutations Matter?" (https://www.sciencebuddies.org/science- ... -mutations) and I'm struggling quite a bit.

The thing I don't quite understand is why some mutations cause a disease while similar mutations don't. For example, Table 3 in the project site has recorded one amino acid change from Valine to Methionine, and this is listed as non-pathogenic (this particular mutation does not cause cystic fibrosis).
However, when filling up the rest of Table 3 with other genetic mutations that ARE pathogenic, I noticed one in particular (this is taken from the NCBI website). Its variant ID is rs397508328, and the amino acid change is from Methionine to Valine. Despite both amino acids being non polar and hydrophobic, Met > Val causes cystic fibrosis. Valine is also one the favorable amino acid substitutions for Methionine.

I find this confusing, as I thought only the drastic amino acid changes (for example, Met > Lys) caused trouble. How do I better understand what changes really matter?
I can't find any answers to this anywhere. Please help! <//3

Side note: My biology project is about gene editing. I'm doing the ScienceBuddies project, but I also need to add an investigatory/research/experiment/case study part to my project related to gene editing. Any ideas?

[rbharambe]

Hello,

That's a great question! Even though Valine and Methionine are similar, the impact of the change depends on the amino acid's specific role in protein structure. A protein's shape depends on how amino acids interact during folding. In your example, Valine might not be essential for folding, so changing it to Methionine has little effect. However, when Methionine is important for folding, switching it to Valine can disrupt the structure, leading to functional issues and potentially drastic effects.

To better understand what changes matter, understanding the chemical composition of the amino acids and protein's folding patterns can help predict whether the change is significant.

I hope that helps!