Mutation: Types, Causes, Impacts and Evolution

1Overview

Every time a cell divides, its entire genome must be copied. A copying job that long will occasionally make errors, and the environment adds damage on top. A change in DNA is called a mutation. Mutations have a bad reputation, from cancer to science-fiction villains, but they are also the original source of every new allele and, over long periods, of the diversity of life. This lesson covers the official content on mutation: its positive, negative and neutral impacts, mutagens and carcinogens, and its role in evolution.

2What a mutation is

A mutation (also called a gene variant or DNA variant) is a permanent change in the DNA sequence of an organism. It can involve one nucleotide or many, and it can affect a single gene or whole chromosomes. Mutations arise in several ways:

• Copying errors. DNA polymerase occasionally inserts the wrong base during replication.
• Damage from mutagens. Chemicals and radiation can damage DNA directly.
• Viral infection can also alter DNA.

Mutations that arise from the normal chemistry inside cells are called spontaneous, and those caused by agents such as chemicals, ultraviolet (UV) light or X-rays are called induced.

Somatic and germline mutations

Where a mutation occurs determines who it affects. Somatic mutations occur in body cells such as skin or muscle. They are not passed to offspring and affect only the cell and its descendants. Germline mutations occur in eggs and sperm (or the cells that make them). They can be passed to offspring and appear in every cell of the resulting person. A change that is new in a child and absent from both parents is called a de novo variant.

3Types of mutations

Changes to a single base or a few bases

The frameshift deserves special attention. The ribosome reads mRNA in groups of three, so adding or losing one or two nucleotides (an insertion or deletion that is not a multiple of three) shifts the reading frame of every codon after that point. Downstream amino acids change, and the protein is usually nonfunctional. An analogy: a sentence made only of three-letter words, THE CAT SAW THE DOG, makes sense when read in groups of three. Deleting the first letter gives HEC ATS AWT HED OG, which is gibberish.

Changes to whole chromosomes

Mutations can also affect chromosome number or structure. Nondisjunction during meiosis produces gametes with an extra or missing chromosome, as in Down syndrome (trisomy 21), covered in the first lesson. Pieces of chromosomes can also be lost, repeated, inverted or moved to another chromosome (translocation).

4Repairing DNA

Cells are not passive victims of copying errors. Several systems detect and fix damage:

1. Proofreading. As DNA polymerase adds each base, it checks the match and removes mismatched bases.
2. Mismatch repair. After replication, repair enzymes find remaining errors, remove the incorrect section of the new strand and resynthesize it correctly.
3. Excision repair. Damaged bases, such as the abnormal links between neighbouring thymine bases (thymine dimers) caused by UV light, are cut out. DNA polymerase fills the gap and DNA ligase seals it.

Because of these systems, many potential mutations never become permanent. When repair fails, the consequences can be serious. People with xeroderma pigmentosum have a defect in excision repair, so UV damage is not fixed, their skin is extremely sensitive to UV light, and the risk of skin cancer is higher. Mutations in repair genes are linked to cancers such as pancreatic and colorectal cancer.

5Mutagens and carcinogens

A mutagen is an agent that increases the rate of mutation. Mutagens include ultraviolet radiation, ionizing radiation such as X-rays, and many chemicals. A carcinogen is a substance or exposure that can cause cancer. The two groups overlap because cancer is caused by changes in genes that alter how cells function, and many carcinogens act by damaging DNA.

The National Toxicology Program’s list of known human carcinogens includes substances such as asbestos, benzene, formaldehyde, radon, aflatoxins, arsenic and cadmium. Chemicals in tobacco smoke, secondhand smoke and ultraviolet radiation from the sun are also identified as cancer-causing exposures.

Cancer is not simply the result of one exposure. Some cancer-causing changes occur naturally when cells divide, and others result from environmental exposures. Being exposed to a carcinogen does not guarantee that cancer will develop: the dose, the duration of exposure, and a person’s genetic background all influence the risk. This is why reducing exposure (sun protection, avoiding tobacco smoke, radon testing) lowers risk without eliminating it.

6Positive, negative and neutral impacts

Mutations are often described by their effect on the organism. These categories depend on the environment as much as on the DNA.

Negative (harmful) mutations

Mutations that reduce or destroy the function of an essential protein can cause disease. Variants in the PAH gene lead to PKU, and variants in the HBB gene lead to sickle cell disease. Cystic fibrosis, hemophilia and many other inherited conditions arise from mutations that were present in earlier generations. Somatic mutations that disable the control of cell division can cause cancer.

Neutral mutations

Most variants do not cause disease. Many have no effect at all: they may be silent substitutions, lie in regions that do not code for protein, or change an amino acid in a way that does not alter function. The code is redundant, which cushions the effect of many substitutions. Common variation that is simply a normal difference among people includes eye colour, hair colour and blood type.

Positive (beneficial) mutations

Beneficial mutations are uncommon, and they are not dramatic. A mutation is beneficial only if it improves survival or reproduction in a particular environment. A clear example comes from bacteria. Germs can change so that they resist antibiotics, and the genes that determine resistance are encoded in DNA. When antibiotics are used, susceptible germs die and resistant ones survive, multiply and spread. The mutation that is beneficial to the bacterium is harmful to a patient being treated. The same change that helps in one environment is neutral or even costly in another.

7Mutation and evolution

Without mutation there would be no new alleles. Mutation is the ultimate source of new alleles, and sexual reproduction then creates new combinations of alleles. Natural selection can only act on variation that already exists in a population, so mutation supplies the raw material on which selection works.

For evolution to occur, the mutation must be in the germline, because only those mutations can pass to the next generation. If the mutation is beneficial, individuals that carry it tend to leave more offspring, and over generations the allele becomes more common in the population. If it is harmful, selection tends to remove it. If it is neutral, its fate depends largely on chance. Over many generations and many mutations, populations can become different from their ancestors, and eventually different species can arise, which later lessons explain.

Evolution through mutation is slow in the sense that any single mutation is rare, but it is fast in the sense that populations are enormous. Bacteria, which reproduce quickly and in vast numbers, show this clearly, as in the spread of antibiotic resistance. A reminder of the connection between mutation and natural selection is found in What is natural selection?.

The next lessons follow this idea: how selection acts on variation in nature (natural selection), and how people direct it deliberately (artificial selection). The ethical and practical issues raised by humans now being able to change DNA directly are the subject of the final lessons. More background on the molecule is in What is DNA?.

8Practice problems with solutions

Problem 1: classify the mutation

The original mRNA codons are GAA-CCU-UUC (glutamic acid, proline, phenylalanine). Classify each change. (a) GAA to GAG: glutamic acid is still coded, so it is silent. (b) CCU to CAU: histidine replaces proline, so it is missense. (c) UUC to UAA: a stop codon appears, so it is nonsense. (d) Deleting the first G gives AAC-CUU-UC, shifting the frame, so it is a frameshift, which changes every later amino acid.

Problem 2: decide who is affected

A skin cell in an adult acquires a mutation after sun exposure. Will the person’s children inherit it? No. This is a somatic mutation, which affects that cell and its descendants only. A mutation in a developing egg would be germline and could be inherited.

Problem 3: judging impact

A mutation in an intron of a gene changes one base, and the protein sequence is unchanged. It is probably neutral. A mutation in the same gene that creates an early stop codon may be harmful, because a shortened protein often does not work.

Summary

• Mutations arise from copying errors and from mutagens, and repair systems fix many of them.
• Effects can be harmful, neutral or (rarely) beneficial, and benefit depends on the environment.
• Mutation is the ultimate source of new alleles, so it is the raw material for evolution.

?Quick check

Try each question first, then reveal the answer.