2.2
Genome Copying Errors
Every time a human cell divides, the DNA polymerase enzymes copy over 3 billion base pairs with high fidelity, to be passed on to the daughter cells.
However, due to the sheer volume of information being duplicated, the DNA polymerase sometimes makes errors while copying. For example, an incorrect base may be added to the newly synthesized strand, such as a cytosine instead of thymine.
In some cases, such changes can be harmful, like the single nucleotide change from GAG to GTG in the beta-hemoglobin gene which causes sickle-shaped red blood cells. This reduces the oxygen-carrying capacity of red blood cells, resulting in sickle cell anemia.
Extra bases may also be added or deleted from the genes. Such mutations are collectively called indels. In cystic fibrosis, a single base added or deleted in the CFTR gene can shift the reading frame such that the gene encodes a defective protein. This protein cannot transport chloride ions out of the lung epithelial cells, resulting in the accumulation of thick, glue-like mucus, which increases the risk of lung infection.
Fortunately, such copying errors occur at low frequency - around 1 error per 100,000 bases.
Additionally, the majority of these errors are rectified during the replication by DNA polymerase enzymes' proofreading activity before they can be passed to the daughter cells, or are fixed after replication by DNA repair enzymes. Nevertheless, in rare cases, errors may escape the repair process and pass on to the next generation.
However, not all mutations are harmful to the organism; most mutations are neutral, and some may confer survival advantages.
Antibiotic resistance is one beneficial trait that can arise via mutation.
For example, the antibiotic fluoroquinolone binds to a bacterial enzyme called DNA gyrase, and inhibits bacterial growth. However, when the genes coding for the enzyme DNA gyrase accumulate random base substitutions, this results in a mutated version of the enzyme. The antibiotic can no longer bind to this mutated enzyme, which leads to the survival and growth of bacteria, even in the presence of antibiotics.
DNA replication is a well-evolved process that copies millions of base pairs with high fidelity during each cell division. Occasionally a wrong base or a long stretch of wrong bases may get added to the daughter strands. If the errors are left unchecked, cells might accumulate several mutations that might endanger their survival. Therefore, the copying errors are checked and repaired at three levels.
- Proofreading - DNA polymerase enzymes, for example, introduce 1 incorrect nucleotide per 100,000 bases. These errors are detected and rectified during the DNA replication itself by DNA polymerase enzymes. These enzymes possess 3'→5' exonuclease activity that excises the incorrect base from the daughter strand and replaces it with the correct nucleotide.
- Mismatch repair - DNA repair enzymes repair the wrong bases or point mutations in the DNA post replication but before mitosis.
- DNA damage repair pathways - DNA is also prone to physical or chemical damage caused by mutagens. DNA damage repair mechanisms operate throughout the cell cycle and can repair point mutations and large-scale genome rearrangements. If the DNA damage is severe, the repair pathway will block cell cycle progression and initiate apoptosis.
In addition to errors during DNA replication, mutations can also be caused by mobile genetic elements called transposons. They are small DNA repeat elements that can jump from one place to another on the DNA strand and disrupt the gene functions at their site of insertion. They can also cause inversions, gene duplication, or create novel genes. Transposons are of two major types: DNA transposons, which transpose directly as DNA, and RNA or retrotransposons, which transpose via an RNA intermediate. Some of these transposons result in target site duplication during their insertion at the new site on the chromosome. Such duplications at the target site can result in gene duplication, which may harm the cell function.
Every time a human cell divides, the DNA polymerase enzymes copy over 3 billion base pairs with high fidelity, to be passed on to the daughter cells.
However, due to the sheer volume of information being duplicated, the DNA polymerase sometimes makes errors while copying. For example, an incorrect base may be added to the newly synthesized strand, such as a cytosine instead of thymine.
In some cases, such changes can be harmful, like the single nucleotide change from GAG to GTG in the beta-hemoglobin gene which causes sickle-shaped red blood cells. This reduces the oxygen-carrying capacity of red blood cells, resulting in sickle cell anemia.
Extra bases may also be added or deleted from the genes. Such mutations are collectively called indels. In cystic fibrosis, a single base added or deleted in the CFTR gene can shift the reading frame such that the gene encodes a defective protein. This protein cannot transport chloride ions out of the lung epithelial cells, resulting in the accumulation of thick, glue-like mucus, which increases the risk of lung infection.
Fortunately, such copying errors occur at low frequency - around 1 error per 100,000 bases.
Additionally, the majority of these errors are rectified during the replication by DNA polymerase enzymes' proofreading activity before they can be passed to the daughter cells, or are fixed after replication by DNA repair enzymes. Nevertheless, in rare cases, errors may escape the repair process and pass on to the next generation.
However, not all mutations are harmful to the organism; most mutations are neutral, and some may confer survival advantages.
Antibiotic resistance is one beneficial trait that can arise via mutation.
For example, the antibiotic fluoroquinolone binds to a bacterial enzyme called DNA gyrase, and inhibits bacterial growth. However, when the genes coding for the enzyme DNA gyrase accumulate random base substitutions, this results in a mutated version of the enzyme. The antibiotic can no longer bind to this mutated enzyme, which leads to the survival and growth of bacteria, even in the presence of antibiotics.
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2.2 : Genome Copying Errors
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