Mutations and Sources of Genetic Variation

What Are Mutations?

A mutation is a change in the base sequence of DNA. Mutations are the ultimate source of all new alleles and therefore of all genetic variation. They can occur spontaneously during DNA replication or be induced by mutagens (e.g. UV radiation, chemical mutagens, ionising radiation).

Types of Gene Mutation

Gene mutations (point mutations) affect one or a few nucleotides within a single gene.

Substitution Mutations

A single base is replaced by a different base. The consequences depend on which amino acid, if any, is affected:

Type	Effect	Example
Silent	The new codon codes for the same amino acid (due to degeneracy of the code)	GCA → GCG (both code for alanine)
Missense	The new codon codes for a different amino acid	GAG → GTG (glutamic acid → valine) — this causes sickle cell anaemia
Nonsense	The new codon is a stop codon	CAG → UAG — polypeptide is truncated

Sickle cell anaemia is the classic AQA example: a single base substitution (A→T) in the sixth codon of the beta-globin gene changes codon 6 from GAG (glutamic acid) to GTG (valine). The hydrophobic valine causes haemoglobin S molecules to polymerise under low oxygen conditions, distorting red blood cells into a rigid sickle shape.

Insertion and Deletion Mutations

An extra base is added (insertion) or a base is removed (deletion) from the DNA sequence. These cause a frameshift — every codon downstream of the mutation is read differently, usually producing a completely non-functional protein. Frameshifts are generally more damaging than substitutions.

If three bases are inserted or deleted together, one amino acid is added or lost, but the reading frame is preserved — these are often less severe. Cystic fibrosis is commonly caused by deletion of three bases (ΔF508), removing a phenylalanine at position 508 of the CFTR protein without causing a frameshift.

Chromosome Mutations

These involve changes to whole chromosomes or large sections:

• Non-disjunction — failure of chromosomes to separate during meiosis, leading to aneuploidy (e.g. trisomy 21/Down syndrome)
• Translocation — a segment of one chromosome breaks off and attaches to a non-homologous chromosome
• Inversion — a segment of chromosome is reversed
• Duplication — a segment is copied, so the chromosome has two copies of a region
• Deletion — a segment is lost entirely

Sources of Genetic Variation

Genetic variation in populations arises from several sources:

1. Mutation

Mutations are the only source of new alleles. Without mutation, there would be no raw material for natural selection. Most mutations are neutral (no effect on fitness), some are harmful, and rarely, some are beneficial. The mutation rate is low (typically 10⁻⁸ to 10⁻⁹ per base pair per generation in humans), but across the entire genome and population, mutations constantly introduce new variation.

2. Meiosis

Meiosis generates new combinations of existing alleles through:

• Independent assortment (metaphase I) — random orientation of bivalents means maternal and paternal chromosomes are distributed independently. For n chromosome pairs, 2ⁿ combinations are possible (2²³ ≈ 8.4 million in humans).

• Crossing over (prophase I) — exchange of DNA between non-sister chromatids of homologous chromosomes at chiasmata. This produces recombinant chromosomes with new combinations of alleles that did not exist on either parental chromosome.

Together, these mechanisms ensure that each gamete is genetically unique.

3. Random Fertilisation

Any sperm can fertilise any egg, creating an enormous number of possible zygote genotypes. This is the third layer of variation arising from sexual reproduction.

4. Random Mating

In populations where mating is random with respect to genotype, alleles are shuffled across generations. Non-random mating (e.g. assortative mating, inbreeding) alters genotype frequencies but does not create new alleles.

Gene Mutations and Protein Function

The effect of a mutation depends on its location and type:

Mutations in coding regions may:

• Change the primary structure of the protein (different amino acid sequence)
• Alter the protein's tertiary structure and therefore its function (e.g. enzyme activity, receptor binding)
• Create a premature stop codon, producing a truncated, non-functional protein
• Have no effect (silent mutation)

Mutations in regulatory regions (e.g. promoter, enhancer) may:

• Increase or decrease the level of gene expression without changing the protein itself
• Alter when or where a gene is expressed

Mutations in splice sites may:

• Cause incorrect splicing of pre-mRNA
• Include an intron or exclude an exon, changing the protein

Mutation and Disease

Many genetic diseases result from specific mutations:

Disease	Gene	Mutation type	Effect
Sickle cell anaemia	HBB (beta-globin)	Missense substitution	Glu→Val at position 6; HbS polymerises
Cystic fibrosis	CFTR	Most commonly ΔF508 (3-base deletion)	Misfolded CFTR protein; impaired Cl⁻ transport
Huntington's disease	HTT	Trinucleotide repeat expansion (CAG)	Expanded polyglutamine tract; toxic protein aggregation
Phenylketonuria (PKU)	PAH	Various (missense, splice site)	Deficient phenylalanine hydroxylase; Phe accumulates

Sickle Cell and Natural Selection

Sickle cell anaemia provides a textbook example of heterozygote advantage (balancing selection):

• HbA/HbA homozygotes have normal haemoglobin but are susceptible to malaria
• HbS/HbS homozygotes have sickle cell disease — severe, often fatal
• HbA/HbS heterozygotes have sickle cell trait — mild or no symptoms, but are resistant to malaria because parasitised red blood cells sickle and are destroyed

In regions where malaria is endemic (e.g. sub-Saharan Africa), the HbS allele is maintained at a higher frequency than expected because heterozygotes have a selective advantage. This is an example of stabilising selection acting on the population.

Variation: Continuous vs Discontinuous

Feature	Discontinuous variation	Continuous variation
Distribution	Distinct categories (no intermediates)	Range of values (normal distribution)
Genetic basis	Usually one or few genes	Polygenic (many genes)
Environment	Little or no environmental effect	Significant environmental influence
Examples	Blood group (ABO), CF carrier status	Height, mass, skin colour, intelligence

Polygenic inheritance — many genes each contribute a small additive effect to the phenotype. Combined with environmental variation, this produces the continuous range of phenotypes seen for most measurable traits.

Exam Tips

• AQA expects you to name specific examples of mutations and their consequences — sickle cell (HBB missense) and cystic fibrosis (CFTR ΔF508) are essential
• When discussing sources of variation, clearly distinguish between sources of NEW alleles (mutation only) and sources of new COMBINATIONS of existing alleles (meiosis, random fertilisation)
• Frameshift mutations are more severe than substitutions — explain why in terms of every downstream codon being altered
• For sickle cell heterozygote advantage, be specific: state the genotypes, phenotypes, and explain why HbS frequency is high in malarial regions