## Overview Welcome to AQA A-Level Biology topic 8.1: Alteration of the Sequence of Bases. This topic is fundamental to genetics and protein synthesis, exploring how tiny changes in our DNA can lead to significant, observable differences in an organism. A gene mutation is a change in the sequence of nucleotide bases in DNA, which can alter the primary structure of a polypeptide. This, in turn, affects the protein's final 3D shape and function. Understanding this causal chain is not just crucial for your biological knowledge; it's a frequent source of high-mark questions in the exam. Examiners expect you to link the molecular change (DNA) to the functional outcome (protein) with precision. This guide will equip you with the key concepts, terminology, and exam strategies to tackle any question on this topic with confidence.  ## Key Concepts ### Concept 1: Gene Mutations - Substitution, Deletion, and Addition A gene mutation is a change in the nucleotide base sequence of a gene. There are three main types you need to know: * **Substitution**: One base is swapped for another. For example, a DNA triplet of GCA becomes GCG. This is a 'point mutation' as it affects a single point in the sequence. * **Deletion**: One or more bases are removed from the sequence. For example, GCA becomes GA. * **Addition**: One or more bases are inserted into the sequence. For example, GCA becomes GCTA. Deletion and addition are known as **frameshift mutations**. Because DNA is read in non-overlapping triplets (codons), adding or removing a base shifts the entire 'reading frame' from that point onwards. This has a major knock-on effect, altering every subsequent codon and therefore every amino acid in the polypeptide chain. Substitutions, by contrast, only affect a single codon.  ### Concept 2: The Consequences of Mutations The effect of a mutation depends on its type and location. * **Silent (Synonymous) Mutations**: A substitution may result in a new codon that still codes for the same amino acid. This is possible because the genetic code is **degenerate** – most amino acids are coded for by more than one codon. For example, both CCG and CCA code for Proline. In this case, the primary structure of the polypeptide is unchanged, and the mutation has no effect. * **Missense Mutations**: A substitution that results in a codon for a different amino acid. This changes the primary structure of the polypeptide. The effect can be minor if the new amino acid has similar properties to the original, or major if it's very different (e.g., changing a non-polar amino acid to a charged one). * **Nonsense Mutations**: A substitution that results in a 'stop' codon. This prematurely terminates translation, leading to a truncated, and almost always non-functional, polypeptide. * **Frameshift Mutations**: As explained above, these change every codon downstream of the mutation, leading to a completely different amino acid sequence and a non-functional protein. ### Concept 3: The Causal Chain - From DNA to Non-Functional Protein This is the most important logical sequence in the topic and is frequently tested in 5-6 mark questions. You must be able to explain the entire process, from the initial mutation to the final outcome, typically a non-functional enzyme.  1. **Change in DNA Base Sequence**: The mutation occurs (e.g., substitution, deletion). 2. **Change in mRNA Codon Sequence**: The altered DNA is transcribed into a complementary mRNA strand, so the codon sequence is now different. 3. **Change in Amino Acid Sequence**: The mRNA is translated at the ribosome. The different codon sequence results in a different sequence of amino acids being joined together. The **primary structure** of the polypeptide is altered. 4. **Change in Bonding**: The primary structure dictates how the polypeptide folds. A different amino acid sequence means the R-groups are in different positions. This alters the position of **hydrogen, ionic, and disulfide bonds** that form between these R-groups. 5. **Change in Tertiary Structure**: With the bonds forming in different places, the polypeptide folds into a different 3D shape. The **tertiary structure** is altered. 6. **Non-Functional Protein**: For an enzyme, the tertiary structure determines the specific shape of the **active site**. If the tertiary structure changes, the active site shape changes and is no longer complementary to its substrate. Enzyme-substrate complexes cannot form, and the enzyme is non-functional. ## Mathematical/Scientific Relationships There are no specific mathematical formulas in this topic. The key relationship is the biological one: the direct causal link between the sequence of bases in DNA and the sequence of amino acids in a protein, which in turn determines the protein's final structure and function. ## Practical Applications Understanding gene mutations is critical for medicine and biotechnology. Many genetic disorders, such as **sickle-cell anaemia** and **cystic fibrosis**, are caused by specific gene mutations. For example, sickle-cell anaemia is caused by a single substitution mutation in the gene for haemoglobin. This changes one amino acid in the beta-globin chain, causing the haemoglobin molecules to stick together and form rigid fibres, deforming the red blood cells into a sickle shape. This demonstrates how a tiny change at the DNA level can have a massive impact on the phenotype of an organism.