Comprehensive Study Notes on Genetic Mutations

Introduction to Mutations

• Mutations are sudden, random changes in the genetic code of an organism.

• Inheritance: Mutations can be inherited if they occur in sex cells (gametes).

• How they occur: Mutations happen primarily during DNA replication when a copy of the DNA is being made. This can occur due to errors in DNA polymerase activity, where an incorrect nucleotide is incorporated, or through chemical modifications of bases that lead to mispairing during subsequent replication. The copied DNA is not identical to the original because the base pairs may be different, changing the gene's structure and the genetic code it carries.

• Where they occur:

  • In somatic cells (body cells): These mutations can lead to diseases like cancer and are not passed on to offspring.

  • In sex cells / gametes (sperm or egg): These mutations can be inherited by the next generation.

Frequency of Mutations and Mutagens

• Frequency: Mutations occur fairly frequently due to the vast number of nucleotides in DNA.

• Human genome size: Humans have about 6 \times 10^9 nucleotides (approximately 6 billion).

• Example of variation: A child can differ from its parents by around ( \text{approximately } 50 \text{)} ) single nucleotide mutations.

• Causes (Mutagens): Mutations can be caused by environmental agents called mutagens.

  • Radiation: Such as X-rays and UV light. UV radiation primarily causes pyrimidine dimers (e.g., thymine dimers), which are covalent bonds between adjacent pyrimidines, disrupting DNA replication. Ionizing radiation (like X-rays and gamma rays) can lead to single and double-strand breaks in the DNA backbone, as well as various base modifications.

  • Chemicals: Including base analogs (molecules that mimic normal nucleotide bases and can be incorporated into DNA during replication, like 5-bromouracil, which can mispair with guanine), intercalating agents (molecules that insert themselves between DNA base pairs, like ethidium bromide, causing frameshifts during replication), and base-modifying agents (chemicals that alter specific bases, like nitrous acid, which can deaminate cytosine to uracil).

  • Microorganisms: Like certain viruses.

• Note: Not everyone exposed to mutagens will suffer a mutation; individuals react differently.

Types of Gene Mutations

• Gene mutations are changes that involve a single or a few base pairs within one gene, altering its structure or sequence.

• Two main types:

  • 2.1. Point Mutations

  • 2.2. Frame-shift Mutations

Types of Gene Mutations (continued)

• 2.1. Point Mutations

  • Definition: A type of gene mutation where a single base is changed or replaced by another base pair.

  • Effect: The change in one base pair results in a change in one base of the mRNA, which then alters the codon. This can have different outcomes depending on the specific change, primarily categorized when a substitution occurs:

    • Silent Mutation: The change in the DNA base results in a new mRNA codon that still codes for the same amino acid. This is possible due to the degeneracy of the genetic code, where multiple codons can specify the same amino acid. As there is no change in the protein sequence, the mutation has no detectable effect on protein function or the organism's characteristics.

    • Missense Mutation: The change in the DNA base results in a new mRNA codon that codes for a different amino acid. This leads to an altered protein. The effect on protein function can vary from negligible to severe, depending on the role of the new amino acid in the protein's structure or active site. For example, Sickle Cell Anaemia is caused by a missense mutation where glutamic acid is replaced by valine in the hemoglobin protein.

    • Nonsense Mutation: The change in the DNA base results in a new mRNA codon that is a premature stop codon (UAA, UAG, or UGA). A stop codon signals the termination of protein synthesis. This leads to a truncated (shortened) protein, which is usually non-functional because it is incomplete and often unstable.

  • Example: Sickle cell anaemia is a genetic disorder caused by a point mutation (specifically, a missense mutation).

  • Types of Point Mutations:

  • Substitution: One nitrogen base is replaced by another, as described above, potentially resulting in one new amino acid, a premature stop codon, or no change in the amino acid sequence.

  • Inversion: One or more DNA triplets are inverted (reversed) within the gene sequence, leading to the alteration of one or more amino acids and changing the local sequence.

• Substitution

  • Definition: A gene mutation where one nitrogenous base is replaced by another. This results in the alteration of only one amino acid or can lead to a silent or nonsense mutation.

  • Conceptual idea: DNA → mRNA → amino acids; a single base change can alter one codon and hence one amino acid in the protein, or signal premature termination, or have no effect due to genetic code degeneracy.

  • Example (illustrative): A base change in a codon can replace one amino acid in the growing polypeptide.

• Inversion

  • Definition: A gene mutation where one or more base triplets are inverted. This results in the alteration of one or more amino acids.

  • Conceptual idea: A triplet sequence is reversed, changing the downstream amino acid sequence.

• 2.2. Frame-shift Mutations

  • Definition: A type of gene mutation where a single base pair is inserted or deleted from the DNA molecule.

  • Effect:

  • This insertion or deletion affects the triplet reading frame (the way codons are read in groups of three).

  • From the point of change onwards, the DNA produces an mRNA sequence that is entirely different from the original.

  • This results in a completely different sequence of amino acids being produced.

  • A new protein is formed that will likely not function as the original protein, often leading to a much more severe consequence than most point mutations due to widespread changes in the amino acid sequence or premature termination.

  • This can lead to significantly altered characteristics.

  • Types of Frame-shift Mutations:

  • Deletion: One or more nitrogen bases are lost, causing all subsequent DNA triplets and amino acids to be altered.

  • Insertion: One or more nitrogen bases are added, causing all subsequent DNA triplets and amino acids to be altered.

• Deletion

  • A gene mutation where one or more nitrogenous bases are lost may result in a frame shift. After such a deletion all the base triplets are altered and consequently also the amino acids.

  • Example representation in transcript: 'C' was lost leading to altered downstream codons and amino acids.

• Insertion

  • A gene mutation where one or more nitrogenous bases are inserted may result in a frame shift. After an insertion, all the base triplets are altered and consequently also the amino acids.

  • Example representation in transcript: 'C' inserted leading to altered downstream codons and amino acids.

• Relationship snapshot

  • Gene Mutations \rightarrow mRNA changes (codons) \rightarrow amino acid changes \rightarrow altered proteins

Effects of Mutations

• Mutations can have various effects on an organism:

  • Harmless/Neutral Mutations: These do not affect the structure or functioning of the organism. They often occur in the non-coding DNA regions or as silent mutations where the amino acid sequence remains unchanged due to the degeneracy of the genetic code. They can still be passed on.

  • Advantageous/Beneficial Mutations: These mutations benefit the organism, helping it to survive, compete, or adapt better to its environment. They are typically passed on and can become more common in a population over time (e.g., mutations conferring antibiotic resistance to bacteria or increased bone density in humans).

  • Harmful Mutations (also called Lethal Mutations): These cause genetic disorders or diseases. Most of these disorders are autosomal recessive (two copies of the recessive allele needed for the condition to appear), but some can be dominant or X-linked.

  • Examples given: Sickle-cell anaemia, Albinism.

Genetic Disorders Caused by Mutations (Detailed Examples)

• Sickle Cell Anaemia

  • Definition: A genetic disorder characterized by abnormal, sickle-shaped red blood cells.

  • Cause: Mutant allele on chromosome 11, specifically a single base substitution (missense mutation) that changes glutamic acid to valine in the beta-globin chain of hemoglobin.

  • Symptoms: Sickle-shaped red blood cells block small blood vessels, reducing blood supply; leads to reduced oxygen and nutrient supply to organs; can cause organ damage (e.g., spleen, kidneys, lungs), stroke, anaemia, severe pain, and increased susceptibility to infections.

  • Treatment: Blood transfusions, pain-relief drugs, hydroxyurea to stimulate fetal hemoglobin production, bone marrow transplant (potential cure but high risk, especially for adults due to immune rejection and donor matching).

• Albinism

  • Definition: A group of genetic disorders characterized by a reduced amount or complete lack of the pigment melanin in the skin, hair, and eyes.

  • Oculocutaneous albinism is the most common type, affecting eyes (oculo) and skin (cutaneous).

  • Cause: Ocular albinism is caused by a mutation of a gene on the X-chromosome (typically the GPR143 gene). Other types involve autosomal genes, such as mutations in the tyrosinase gene (TYR) for Type 1 oculocutaneous albinism, which is essential for melanin production.

  • Symptoms: Poor vision (including nystagmus, photophobia, and reduced visual acuity) and very light skin; light skin increases sunburn and skin cancer risk due to lack of melanin protection; development may be slower due to visual problems, but intelligence is normal.

  • Treatment: No cure; management involves sun protection creams, protective clothing, and specialized eyewear to help manage photophobia and improve vision. Social stigma can be addressed through education and support groups.

Screening for Genetic Disorders (General)

• DNA testing can identify specific gene mutations.

• Prenatal diagnosis is recommended in cases where both parents are known carriers of a genetic disease to assess risk to the unborn child, or if there is a family history of a genetic disorder.

Genetic Testing and Counselling

• Genetic Testing

  • Definition: Medical tests performed to identify changes in chromosomes, genes, or proteins, which can confirm or rule out a suspected genetic condition or determine a person's risk of developing or passing on a genetic disorder.

  • Uses:

  • Diagnose disorders in unborn babies (e.g., through amniocentesis or chorionic villus sampling).

  • Identify individuals who are carriers of a genetic disorder, who may not show symptoms but can pass the altered gene to their children.

  • Predict the chances of someone developing a genetic disease later in life (presymptomatic testing).

  • Determine the risk of a couple passing a genetic disorder to their children (preconception or preimplantation genetic diagnosis).

• Genetic Counselling

  • Definition: A process that takes place after genetic testing with trained genetic counsellors to help people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease.

  • Importance: Provide parents/couples with accurate information about genetic disorders, inheritance patterns, and risk assessment; present all available options for testing, management, and family planning; counsel and support in making informed decisions about genetic conditions based on their personal and ethical beliefs.

The Human Genome Project (HGP)

• What it is: Genome refers to all the genes (and non-coding DNA) present in a cell of an organism, representing the complete set of genetic instructions.

• The HGP was a research effort (1990–2003) to map and understand all the genes of Homo sapiens, determining the sequence of all the approximately three billion nucleotide base pairs.

• Size and gene count:

  • Humans have over 3 \times 10^9 base pairs.

  • Approximately 2.0 \times 10^4 to 2.5 \times 10^4 genes.

• Impact of HGP:

  • Provided a fundamental basis for research in medicine, biotechnology, agriculture, and environmental science by creating a reference sequence for the human genome.

  • Enables more accurate diagnosis, treatment, management, and prevention of genetic diseases through the identification of disease-causing genes and personalized medicine approaches.

  • Helps predict the risk of disease in individuals and their future offspring by understanding genetic predispositions.

  • Aims to reduce the cost of medical care in the long term by improving understanding and targeted treatments, leading to more effective interventions and preventive strategies.

Key Terminology

• Mutations: Sudden, random changes in the genetic code of an organism which can be inherited.

• Point mutation: A mutation affecting only one or very few nucleotides in a gene sequence, including substitutions, inversions, and their specific outcomes like silent, missense, or nonsense mutations.

• Frame-shift Mutation: A genetic mutation caused by a deletion or insertion of a non-multiple-of-three number of nucleotides in a DNA sequence that shifts the way the sequence is read, leading to a completely altered protein product.

• Silent mutations: A type of point mutation where a change in a single DNA base pair does not change the amino acid sequence of the protein, due to the redundancy of the genetic code.

• Missense mutations: A type of point mutation where a change in a single DNA base pair results in the substitution of one amino acid for another in the protein.

• Nonsense mutations: A type of point mutation where a change in a single DNA base pair results in a premature stop codon, leading to a truncated and often non-functional protein.

• Neutral mutations: Mutations where the structure and functioning of the organism are not affected.

• Advantageous mutations: These mutations benefit the organisms.

• Albinism: Refers to a group of genetic disorders characterized by a reduced amount or complete lack of the pigment melanin.

Practice Questions and Solutions (Selected)

• Q1: A genetic disorder characterized by the absence of a blood clotting factor is called…

  • A. Albinism B. Sickle cell anaemia C. Haemophilia D. Down syndrome

  • Answer: C

• Q2: The genetic disorder that is caused by a mutant allele on chromosome number 11 is called…

  • A. Albinism B. Sickle cell anaemia C. Haemophilia D. Down syndrome

  • Answer: B

• Q3: The genetic disorder that results in poor vision and light skin is called…

  • A. Albinism B. Sickle cell anaemia C. Haemophilia D. Down syndrome

  • Answer: A

• Q4: Amniocentesis is a screening method for the genetic disorder…

  • A. Albinism B. Sickle cell anaemia C. Haemophilia D. Down syndrome

  • Answer: D

• Q5: The type of mutation that causes the length of the DNA to increase is…

  • A. Point mutation B. Frame shift mutation C. Chromosomal aberrations D. None of the above

  • Answer: B

• Q6: The type of mutation that is brought about by a substitution is…

  • A. Point mutation B. Frame shift mutation C. Chromosomal aberrations D. None of the above

  • Answer: A

• Q7: When changes in the normal structure of chromosomes occur this is called…

  • A. Point mutation B. Frame shift mutation C. Chromosomal aberrations D. None of the above

  • Answer: C

• Q8: The type of gene mutation in which adenine is lost/deleted from a DNA base triplet is…

  • A. Frame shift mutation B. Point mutation C. Both A and B D. Neither A nor B

  • Answer: A

• Q9: The type of gene mutation where only one nitrogenous base is replaced with another in the mRNA template is…

  • A. Frame shift mutation B. Point mutation C. Both A and B D. Neither A nor B

  • Answer: B

• Q10: The mutation that has no effect on the structure and functioning of the organism which possesses them is called…

  • A. Harmful mutations B. Lethal mutations C. Neutral mutations D. Fixed mutations

  • Answer: C

• Q11: An example of an advantageous mutation is…

  • A. Harmful mutations B. Lethal mutations C. Neutral mutations D. Fixed mutations

  • Answer: D

• Q12: The types of harmless mutations are…

  • A. lethal mutations B. Neutral mutations C. Fixed mutations D. B and C

  • Answer: B and C

• Q13: Lethal mutations are also called…

  • A. Harmful mutations B. Advantageous mutations C. Neutral mutations D. Fixed mutations

  • Answer: A

• Q14: The type of chromosomal aberration where a part of a chromosome is left out is…

  • A. Deletion B. Insertion C. Inversion D. Translocation

  • Answer: A

• Q15: The type of chromosomal aberration where a part of a chromatid breaks off and attaches to its sister chromatid is …

  • A. Deletion B. Insertion C. Inversion D. Translocation

  • Answer: D

• Q16: The type of chromosomal aberration where a part of the chromosome breaks off and reattaches backwards is…

  • A. Deletion B. Insertion C. Inversion D. Translocation

  • Answer: C

• Q17: The type of chromosomal aberration where a part of a chromosome breaks off and is added to a different chromosome is…

  • A. Deletion B. Insertion C. Inversion D. Translocation

  • Answer: D

• Q18: The alteration of a gene by UV radiation is called…

  • A. Replication B. Mutation C. Protein synthesis D. Mitosis

  • Answer: B

• Q19: The genetic disorder that is sex-linked is…

  • A. Colour blindness B. Down syndrome C. Both A and B D. Neither A nor B

  • Answer: A

• Q20: The disease caused by uncontrolled cell division is…

  • A. Cancer B. Sickle cell anaemia C. Haemophilia D. None of the above

  • Answer: A

References in the Source Transcript

• The Human Genome Project (HGP) duration: 1990–2003.

• Visual references