Gene Expression, Mutations, and Genetic Variation

Gene Expression and Mutations

Protein Synthesis: Gene Expression

• Genes and Proteins: Humans have approximately $20,000$ genes, each coding for a specific protein. This is analogous to a "gene cookbook" with $20,000$ recipes, where expressing a gene means making that specific recipe.
• Two Steps to Protein Synthesis/Gene Expression:
  1. Transcription
  2. Translation

Step 1: Transcription

• Definition: The process of converting or reading DNA to make an mRNA (messenger RNA) molecule.
• Location: Occurs in the nucleus, where DNA is located.
• Initiation: The process begins at a specific DNA sequence called the promoter, which signals the enzyme to start.
• Enzyme Involved: RNA polymerase is the enzyme responsible for building the mRNA molecule.
• DNA Template Strand: Only one side of the DNA double helix, the template strand, is read to synthesize mRNA. Knowing one strand's sequence allows the deduction of the complementary strand.
• Base Pairing Rules (DNA to mRNA):
  • DNA A (Adenine) pairs with mRNA U (Uracil) (not T, because RNA contains U instead of T).
  • DNA T (Thymine) pairs with mRNA A (Adenine).
  • DNA C (Cytosine) pairs with mRNA G (Guanine).
  • DNA G (Guanine) pairs with mRNA C (Cytosine).
• Analogy: Transcription is like making a copy of a specific recipe page from the cookbook to take home, rather than taking the whole cookbook.

Step 2: Translation

• Definition: The process of converting the mRNA copy into a protein.
• Location: Occurs in the cytoplasm, specifically at a ribosome.
• mRNA Transport: The mRNA copy made during transcription leaves the nucleus and travels to the cytoplasm.
• Ribosome Function: The ribosome scans and reads the mRNA molecule.
• Start Codon: Protein synthesis begins when the ribosome encounters the start codon on the mRNA. The universal start codon is AUG, which also codes for the amino acid methionine (Met).
• tRNA (transfer RNA):
  • Function: tRNA molecules act as adapters, bringing specific amino acids to the ribosome based on the mRNA sequence.
  • Anticodon: Each tRNA has an anticodon, a three-nucleotide sequence that is complementary to a specific codon on the mRNA.
  • Amino Acid Attachment: Each tRNA carries a specific amino acid.
• Process of Protein Elongation:
  1. The ribosome receives an mRNA codon.
  2. A tRNA with a complementary anticodon and its specific amino acid binds to the mRNA codon.
  3. A second tRNA arrives with its amino acid for the next mRNA codon.
  4. The ribosome facilitates the formation of a peptide bond between the amino acids brought by the adjacent tRNAs.
  5. The first tRNA detaches, and the ribosome moves along the mRNA, allowing the next tRNA to bring its amino acid, linking them sequentially into a growing polypeptide chain.
• Stop Codon: The process continues until the ribosome reaches a stop codon on the mRNA. There are no tRNAs that correspond to stop codons, so protein synthesis terminates. The polypeptide chain is then released and folds into its functional protein structure.

Using the Codon Table

• Codons and Amino Acids: Codons are three-nucleotide sequences on mRNA that specify which amino acid should be added to the polypeptide chain.
• Examples:
  • AUG codes for Methionine (Met) and is the start codon.
  • GAC codes for Aspartic acid (Asp).
  • UAU codes for Tyrosine (Tyr).
• Test Information: A codon table is provided in exams; memorization is not required.
• Important Practice Tip: When using a codon table, always read the mRNA codons, not the tRNA anticodons. The codon table specifies amino acids based on mRNA sequences.

Genetic Variation and Mutations

Human Genetic Similarity

• Humans are $99.9\%$ genetically identical; only a $0.1\%$ difference exists between individuals (unless identical twins).
• Despite this small percentage, $0.1\%$ of $3.2$ billion base pairs (the size of the human genome) still represents a significant number of differing base pairs, accounting for individual differences.

Reasons for No Observable Effect from DNA Differences

Even with DNA differences, sometimes there is no visible change in an individual due to several factors:

1. Redundant Codons (Redundancy):
   • Multiple codons can code for the same amino acid. For example, GUC and GUA both code for Valine.
   • If a DNA mutation changes a codon from GUC to GUA, the same amino acid (Valine) is still incorporated into the protein, resulting in no change to the protein's function or the organism's phenotype.
   • Analogy: Receiving different ingredients (GCC vs. GCA) that still lead to the same result (chicken enchilada protein) means the final product is unchanged.
2. Mutations in Non-Coding Regions or Unused Genes:
   • If a mutation occurs in a gene that is not currently being expressed (e.g., in one of the $970$ "recipes" not being used from a $1,000$ recipe cookbook), it will have no observable effect because the corresponding protein is not made.
   • Similarly, mutations in non-coding regions of DNA (e.g., introns or regulatory sequences that don't affect expression) often have no direct observable impact.

Mutations Defined

• Definition: Any change in the DNA sequence.
• Types of Changes: Additions, deletions, or swaps of nucleotide letters.
  • Example: Original sequence ATCG mutates to ATTCG (an A was added).
• Origin of Mutations:
  • Spontaneous Mutations: Occur naturally, often during DNA replication (e.g., errors as DNA replicates at a rate of $100,000$ base pairs per second).
  • Induced Mutations: Caused by external factors called mutagens.
    • Mutagen: Anything that causes a mutation (e.g., chemicals, radiation).
    • Historical Example: In the 1960s/70s, scientists purposefully exposed plants to radiation to induce mutations and observe potential useful traits.

Effects of Mutations

Mutations can have good, bad, or no (null) effects on an individual's health:

• Bad Mutations:
  • Sickle Cell Disease: A single letter change in DNA (TTC to TAC) leads to a change in one amino acid (Glutamic acid to Valine). This alteration causes red blood cells to deform into a sickle shape.
    • Normal Red Blood Cells: Biconcave disc shape, carry oxygen efficiently to cells for energy production (lack of oxygen leads to cell death).
    • Sickle Red Blood Cells: Malformed, carry less oxygen, are prone to clumping together, which can block blood vessels (leading to ischemia, a lack of oxygen/blood flow causing pain).
    • Symptoms: Fatigue (due to less oxygen/energy) and pain throughout the body.
    • Genetic Basis: Autosomal recessive disorder, meaning an individual must inherit two copies of the recessive allele to have the disease.
    • Prevalence: More common in African Americans.
    • Evolutionary Advantage (in Africa): The persistence of the sickle cell allele is due to its protective effect against malaria in heterozygous carriers (one normal allele, one sickle cell allele). Individuals with normal hemoglobin are susceptible to malaria, while those with sickle cell disease suffer ill effects from the disease itself. Heterozygotes are resistant to malaria and do not typically suffer severe sickle cell symptoms, making them the most successful in malaria-prone environments.
  • Tay-Sachs Disease: A mutation affecting an enzyme responsible for fat breakdown in the brain, leading to severe neurological damage.
• Good Mutations:
  • Some individuals have a DNA mutation that makes them immune to the HIV virus, as their cells cannot be entered by the virus. This is considered a beneficial health mutation.
• Null (No Effect) Mutations: Most mutations have no significant impact on health.
  • Example: Differences in hair type or eye color typically do not affect health.
• Pleiotropy: A genetic condition where one gene affects multiple, seemingly unrelated phenotypic traits (e.g., albinism, where a single gene mutation can affect skin, hair, and eye pigmentation, as well as vision).

DNA Repair Mechanisms

• Spell-Check Analogy: The body has repair enzymes that act like a spell-check system for DNA, detecting and correcting errors.
• Efficiency: These enzymes are highly efficient, catching approximately $99\%$ of all DNA replication mistakes.
• Remaining Errors: Despite repair mechanisms, some mistakes still occur, contributing to mutations.

Protection Against Disease from Mutations

1. Redundant Codons: As discussed, if a mutation results in a redundant codon, the same amino acid is incorporated, preserving protein function.
2. Two Copies of Chromosomes: Most genes are present on two copies of chromosomes (one from each parent).
   • If one copy of a gene has a harmful mutation, the other healthy copy can often compensate, preventing the manifestation of the disease.
   • Exception: X-linked Traits in Males: Normal males (XY) only have one X chromosome. If a harmful mutation occurs on their single X chromosome, there is no second X chromosome to provide a healthy copy, making them more susceptible to X-linked recessive disorders like muscular dystrophy and color blindness.

Sex Chromosome Variations

• Normal Sex Chromosomes:
  • Female: XX
  • Male: XY
• Other Sex Chromosome Combinations (Non-Normal):
  • XO (Turner Syndrome): Individuals are typically female, often with short necks, some cognitive difficulties, and sterility.
  • XXX (Poly-X): Female, generally with fewer overt issues than Turner Syndrome.
  • XXY (Klinefelter's Syndrome): Male, often characterized by