Describe types of mutation (point, frameshift, chromosomal) and the sources of genetic variation including meiosis, fertilisation and mutation, and explain the consequences of mutations for phenotype and population polymorphism

What this dot point is asking

QCAA wants you to define the main classes of mutation, describe how each affects the protein product, list and explain the sources of variation in a sexually reproducing population, and connect mutations to the population concept of polymorphism. Worked examples on a short mRNA sequence are common.

The answer

Variation is the raw material of evolution. A population that is genetically uniform cannot adapt. Variation arises through random changes in DNA (mutation) and is then reshuffled into new combinations every generation through meiosis and fertilisation.

Types of mutation

A mutation is a heritable change in the DNA sequence of an organism. Mutations can occur in body cells (somatic, not inherited) or in gametes (germline, passed to offspring).

Point mutations. A change at a single base pair.

• Substitution. One base is replaced by another.
  • Silent. The new codon codes for the same amino acid (degeneracy of the code), so the protein is unchanged.
  • Missense. The new codon codes for a different amino acid. The protein may be partially or fully functional. The classic example is sickle cell anaemia, where GAG codes for valine instead of glutamate in the beta haemoglobin chain.
  • Nonsense. The new codon is a stop codon. The protein is truncated and usually non-functional.

Insertions and deletions (indels). Bases are added or removed.

• If the number of bases inserted or deleted is not a multiple of three, every codon downstream of the change is shifted. This is a frameshift mutation, and the entire downstream protein sequence is wrong, usually with a premature stop within a few codons. Cystic fibrosis is often caused by an in-frame three-base deletion (delta F508), which is unusually mild for an indel precisely because it is in frame.

Chromosomal mutations. Changes affecting whole sections of chromosomes, or whole chromosomes.

• Deletion. A segment of a chromosome is lost.
• Duplication. A segment is copied, creating extra copies of the affected genes. Gene duplications are an important raw material for evolution because one copy can mutate freely while the original keeps doing its job.
• Inversion. A segment is reversed end-to-end. The genes are still present but their orientation and regulation may change.
• Translocation. A segment moves to a non-homologous chromosome. Chronic myeloid leukaemia is caused by a translocation between chromosomes 9 and 22 producing the Philadelphia chromosome.
• Non-disjunction. Chromosomes fail to separate properly in meiosis. The resulting gamete has an extra or missing chromosome (aneuploidy). Down syndrome (trisomy 21) is the best-known example.

Causes of mutation

• Replication errors. DNA polymerase makes about one mistake per billion bases despite proofreading. With three billion bases in a human genome, every cell division still introduces a few errors.
• Spontaneous chemical change. Tautomeric shifts and deamination of cytosine to uracil cause base changes.
• Mutagens.
  • Radiation. Ultraviolet light forms thymine dimers; ionising radiation (X-rays, gamma rays) causes double-strand breaks.
  • Chemical mutagens. Benzene, tobacco smoke, polycyclic aromatic hydrocarbons, certain pesticides.
  • Biological agents. Some viruses insert into the genome (HPV in cervical cancer).

Sources of genetic variation in sexually reproducing populations

Three processes shuffle existing variation into new combinations every generation, and one process creates new variation.

Meiosis: independent assortment. During metaphase I, each pair of homologous chromosomes lines up independently. Each gamete therefore inherits a random mix of maternal and paternal chromosomes. With n equals 23 in humans, 2 to the 23 (over 8 million) chromosome combinations are possible per gamete.

Meiosis: crossing over. During prophase I, homologous chromosomes pair (synapsis) and exchange segments at chiasmata. This produces recombinant chromatids carrying allele combinations not present in either parent.

Random fertilisation. Any sperm can fertilise any egg. Combined with independent assortment alone, this produces over 70 trillion genetically distinct offspring possibilities per couple, before considering crossing over.

Mutation. All three of the above only reshuffle existing alleles. A new allele can only arise by mutation. Mutation is therefore the ultimate source of variation; meiosis and fertilisation are the proximate shufflers.

Mutations, phenotype and polymorphism

The effect of a mutation on phenotype depends on:

• Location. Mutations in coding regions, splice sites or regulatory regions are more likely to be visible. Mutations in introns or intergenic regions are often silent.
• Type. Substitutions can be silent, missense or nonsense. Indels in coding regions are usually frameshifts.
• Zygosity. A recessive mutation needs to be inherited from both parents to express.
• Cell type. Somatic mutations affect only the descendant cells in that individual (cancer, mosaicism); germline mutations are passed to offspring.

Polymorphism. When two or more alleles of a gene exist in a population above a low frequency (usually defined as one per cent), that gene is polymorphic. Polymorphism is the population-level signature of accumulated mutations that have not been removed by natural selection. The ABO blood group, MN blood group and many single nucleotide polymorphisms (SNPs) used in forensic DNA profiling are examples.

Beneficial, neutral and harmful. Most mutations are neutral (in silent regions or are silent substitutions). A small fraction are harmful, and rarer still are beneficial. Beneficial mutations are the substrate of adaptive evolution.

Common traps

Treating all point mutations as harmful. The degenerate genetic code means many substitutions are silent.

Forgetting that crossing over and independent assortment do not create new alleles. They only recombine existing alleles into new combinations.

Confusing aneuploidy with polyploidy. Aneuploidy is one missing or extra chromosome (trisomy 21). Polyploidy is full extra sets of chromosomes (common in flowering plants).

Calling all chromosomal mutations lethal. Many translocations, inversions and duplications are tolerated, especially in heterozygotes.

Ignoring somatic mutations. They drive cancer even though they are not heritable across generations.

In one sentence

Mutation is a heritable change in DNA ranging from a single base substitution that may be silent, missense or nonsense, through frameshift indels, to whole chromosome rearrangements and non-disjunction; combined with the reshuffling of existing alleles by independent assortment, crossing over and random fertilisation, mutation provides the genetic variation that natural selection acts on and is the ultimate cause of the polymorphism seen in real populations.