Types of Genetic Mutations Lesson: Key Concepts & More

Lesson Overview

• Causes of Genetic Mutations
• Point Mutations (Base Substitutions)
• Frameshift Mutations (Insertions and Deletions)
• Chromosomal Mutations (Large-Scale Changes)

Genetic mutations are permanent changes in the DNA sequence of an organism. DNA (deoxyribonucleic acid) contains the instructions for building proteins, so altering these instructions can have significant consequences. Mutations range from small changes in a single gene to large-scale alterations of chromosomes. These changes are the raw material for genetic variation and evolution, but they can also lead to genetic disorders or cell malfunction. Importantly, not all mutations are harmful-many have no effect on the organism (neutral mutations), and a few may even be beneficial under certain conditions. 

In order to understand how mutations affect organisms, it is important to recall how genes encode proteins. Genes are segments of DNA that are transcribed into messenger RNA (mRNA) and then translated into proteins. The genetic code is read in groups of three DNA bases (triplets), called codons, each of which corresponds to a specific amino acid (or a start/stop signal) during protein synthesis. Because the code is read in a fixed reading frame (non-overlapping groups of three), any change in the nucleotide sequence can potentially alter the codons and thus the amino acid sequence of the protein. However, due to the genetic code's redundancy (multiple codons code for the same amino acid), some single-base changes might not change the protein at all, while others can drastically change it.

Causes of Genetic Mutations

Mutations can arise in different ways. Some mutations occur spontaneously due to natural processes, while others are triggered by environmental factors:

• Spontaneous mutations: These occur naturally from errors in DNA replication or repair. Even though cells have proofreading enzymes, occasionally the wrong nucleotide is inserted or a small loop forms causing an extra or missing base. Most replication mistakes are corrected, but those that escape repair become permanent changes in the DNA. Spontaneous mutations are the baseline source of genetic variation.
  
• Induced mutations (Mutagens): Exposure to certain physical or chemical agents can increase the mutation rate. Any such agent is called a mutagen. For example, ultraviolet (UV) radiation from sunlight can cause abnormal bonds (like thymine dimers) in DNA; high-energy radiation such as X-rays can break DNA strands; and chemicals like tobacco smoke carcinogens or heavy metals (lead, mercury) can damage DNA or interfere with replication. These mutagens can alter nucleotide sequences or disrupt the DNA structure, leading to mutations. Notably, some mutagens (like certain chemicals) are also carcinogens because the mutations they cause can lead to cancer.

Note: Mutations that occur in reproductive cells (sperm or egg) are called germline mutations, and these can be passed on to offspring. In contrast, mutations in body (somatic) cells are not inherited; they affect only the individual (for example, a mutation in one cell can lead to a cancerous tumor, but it would not be present in the person's children).

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Point Mutations (Base Substitutions)

Point mutations are changes that affect a single nucleotide (base) in the DNA sequence of a gene. In most cases, this means one base is substituted for a different base at a particular position in the gene. For example, an adenine (A) might be replaced by a guanine (G) at one spot. This small change affects only one "point" in the gene's sequence.

Even though point mutations alter only one base, they can have varying effects on the protein encoded by the gene. The outcome depends on whether the base change alters the amino acid specified by the codon. There are three possible effects of a base substitution point mutation:

• Silent mutation: The DNA change still codes for the same amino acid, so the protein's amino acid sequence remains unchanged. This is possible because the genetic code is redundant (for instance, the codons GAA and GAG both specify glutamic acid, so a mutation between them is silent in terms of protein sequence). Silent mutations typically occur when the substitution is in the third base of a codon, and they generally have no effect on the organism.
  
• Missense mutation: The base substitution changes the codon to one that encodes a different amino acid. As a result, one amino acid in the protein is altered to another. This single amino acid change can have little effect or a large effect on the protein's function, depending on where in the protein it occurs and how different the new amino acid is. For example, in sickle-cell anemia a point mutation in the hemoglobin β-chain gene changes a codon from GAG (glutamic acid) to GTG (valine), causing the red blood cells to form an abnormal "sickle" shape. This missense mutation alters the protein's properties and leads to disease.
  
• Nonsense mutation: The base substitution changes a codon from one that encodes an amino acid to a stop codon (termination signal). Stop codons (such as "TAA", "TAG", or "TGA" in DNA) signal the ribosome to stop translation. A nonsense mutation therefore causes the protein to terminate prematurely at that mutation site – the protein is truncated (shortened) and likely nonfunctional because essential amino acids after that point are missing. Nonsense mutations (also called stop mutations or chain termination mutations) often have severe effects, especially if the stop occurs early in the gene (leading to a very incomplete protein).

The table below illustrates these types of point mutations with an example. Consider an original DNA codon "CAA", which codes for the amino acid glutamine (Gln):

Frameshift Mutations (Insertions and Deletions)

Sometimes genetic mutations involve the addition or removal of nucleotides rather than a simple substitution. An insertion adds one or more extra nucleotide bases into the DNA sequence, and a deletion removes one or more bases. If the number of bases inserted or deleted is not a multiple of three, the result is a frameshift mutation – meaning the reading frame of the gene is shifted. Since codons are read in threes, adding or deleting bases changes how all subsequent codons are grouped.

Frameshift mutations typically have dramatic consequences for the protein. Because the grouping of bases is thrown off, every codon downstream of the mutation is different from the original. This usually leads to a completely altered sequence of amino acids and often introduces a premature stop codon as well (since the shifted reading frame is likely to encounter a stop signal at some point in the wrong place). The resulting protein is usually nonfunctional due to the extensive changes and truncation.

For example, consider the sentence "THE FAT CAT ATE THE RAT" as an analogy for a gene (with each three-letter word representing a codon). If the first letter 'T' is removed, the sentence reads as "HEF ATC ATA TET HER AT...", which is gibberish. Similarly, deleting one nucleotide in a DNA sequence shifts the triplet reading frame and scrambles the message. Inserting an extra letter would have a comparable effect by misaligning the word (codon) boundaries.

Both insertions and deletions can cause frameshifts. However, if the number of nucleotides inserted or deleted is a multiple of three, the reading frame is preserved because full codons (whole triplets) are added or removed instead of partial codons. Such a mutation is called an in-frame insertion or in-frame deletion (as opposed to a frameshift). In-frame insertions or deletions add or remove one or more complete amino acids but leave the rest of the protein sequence unchanged. For instance, a common mutation that causes cystic fibrosis is the deletion of three bases (one codon) in the CFTR gene; this removes a single amino acid from the CFTR protein without altering the reading frame.

Frameshift mutations are often very harmful. Many genetic diseases are caused by frameshifts; for example, certain mutations in the gene for the enzyme hexosaminidase A (HEXA) that cause Tay-Sachs disease are small insertions or deletions that disrupt the reading frame, leading to a nonfunctional enzyme.

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Chromosomal Mutations (Large-Scale Changes)

Not all mutations are confined to single nucleotides. Chromosomal mutations involve large segments of DNA, including entire genes or multiple genes, and can even affect the structure or number of whole chromosomes. These mutations usually occur due to errors in meiosis (the cell division that produces sperm and eggs) or through DNA damage (such as breaks) that are improperly repaired. Because chromosomal mutations affect many genes at once, they often have significant effects on an organism.

Some key types of structural chromosomal mutations include:

• Deletion (chromosomal): A portion of the chromosome is lost or missing. This means that many nucleotides – potentially dozens of genes – are removed. Chromosomal deletions can cause severe consequences because essential genes may be lost. (For example, a deletion on the short arm of chromosome 5 causes Cri-du-chat syndrome, a developmental disorder.)
  
• Duplication: A segment of the chromosome is copied and inserted, leading to a repeat of that region. This results in extra genetic material. Having an extra copy of genes can disrupt development by unbalancing gene dosage.
  
• Inversion: A segment of a chromosome breaks off and reattaches in the reverse orientation (flipped 180 degrees). In an inversion, no genetic material is gained or lost, but the order of genes in that segment is reversed. Often inversions are harmless, but they can disrupt a gene at the breakpoints or cause fertility problems if they interfere with pairing of chromosomes during meiosis.
  
• Translocation: A segment from one chromosome breaks and attaches to a different, non-homologous chromosome. In a reciprocal translocation, two chromosomes exchange pieces. Translocations rearrange genetic material to new locations. If no genes are disrupted or lost, a translocation can be "balanced" and the individual may be healthy, but problems can arise in offspring or if a gene's regulation is altered. Certain cancers are associated with translocations (for instance, chronic myelogenous leukemia is caused by a specific translocation between chromosomes 9 and 22).
  

In addition to these structural changes, mutations can also affect whole chromosomes in terms of their number. Nondisjunction is an error in chromosome separation during meiosis that results in gametes with an abnormal number of chromosomes. Fertilization involving such gametes leads to aneuploidy – a condition of having extra or missing chromosomes. For example, Down syndrome is caused by an extra copy of chromosome 21 (trisomy 21), and Turner syndrome results from a missing X chromosome (monosomy X); although aneuploidy is not a change in the DNA sequence, it is a chromosomal mutation that can have major effects on an organism's development.

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