Genetic polymorphisms

Polymorphisms - It's Just a Phase

• Genetic Polymorphism: A DNA sequence variation present in > 1% of a population. These are common and often phenotypically silent.
• Types of Polymorphisms:
  • Single Nucleotide Polymorphism (SNP): Most common; a single base-pair substitution. Key in pharmacogenomics (e.g., CYP450 variations).
  • Insertions/Deletions (Indels): Small-scale gain or loss of nucleotides.
  • Copy Number Variation (CNV): Duplication or deletion of large DNA segments (≥1kb).
  • Variable Number Tandem Repeats (VNTRs): Repeating DNA sequences; basis for DNA fingerprinting.

⭐ SNPs account for ~90% of all human genetic variation and are crucial for personalized medicine approaches.

Hardy-Weinberg - Population Math Magic

Calculates genotype and allele frequencies in a non-evolving population.

• Allele Frequency: $p + q = 1$
• Genotype Frequency: $p^2 + 2pq + q^2 = 1$

📌 Assumptions for equilibrium: No Mutation, No Migration, No Natural Selection, Random Mating, and a Large Population.

⭐ For autosomal recessive diseases, the frequency of affected individuals is $q^2$. The carrier frequency ($2pq$) can be estimated as $2q$ when the disease is rare (as $p ≈ 1$).

Clinical Impact - Code Gone Wild

• Pharmacogenomics: Individual genetic variations altering drug response.

  • CYP450 Enzymes: Key in drug metabolism. Variants can be:
    • Poor Metabolizers: ↑ Drug levels, ↑ toxicity risk.
    • Ultrarapid Metabolizers: ↓ Drug efficacy, may need ↑ dose.
  • Examples:
    • CYP2D6: Codeine (prodrug) requires conversion to morphine. Poor metabolizers get no pain relief.
    • CYP2C19: Clopidogrel (prodrug) activation. Poor metabolizers have ↑ risk of stent thrombosis.
    • TPMT: Azathioprine metabolism. Low activity leads to ↑ myelosuppression.

• Disease Susceptibility: SNPs can ↑ risk for specific conditions.

  • Factor V Leiden: SNP in F5 gene → hypercoagulability (↑ DVT risk).
  • Alpha-1 Antitrypsin Deficiency: Leads to early-onset panacinar emphysema.

⭐ The Factor V Leiden mutation is a single point mutation ($G o A$) resulting in an Arg506Gln substitution, making Factor Va resistant to cleavage by activated protein C.

Linkage Disequilibrium - Sticking Together

• Definition: The non-random association of alleles at different loci on the same chromosome. These alleles are inherited together (as a haplotype) more often than predicted by random chance.
• Mechanism: Occurs when loci are physically close, reducing the probability of being separated by recombination. LD decays over generations.
• Application: Crucial for Genome-Wide Association Studies (GWAS), which use marker alleles (SNPs) to pinpoint nearby, ungenotyped, disease-causing variants.

⭐ LD allows us to "scan" the genome for disease associations. If a specific SNP is more common in people with a disease, it suggests a disease-causing gene is likely located nearby on the same haplotype block.

High‑Yield Points - ⚡ Biggest Takeaways

• Single Nucleotide Polymorphisms (SNPs) are the most common genetic variations, crucial for pharmacogenomics and disease risk.
• Restriction Fragment Length Polymorphism (RFLP) detects DNA sequence variations that alter restriction enzyme cut sites.
• Variable Number of Tandem Repeats (VNTRs) and Short Tandem Repeats (STRs) are hypervariable loci used for DNA fingerprinting.
• Copy Number Variations (CNVs) are large DNA deletions or duplications linked to autism and other complex diseases.
• Polymorphisms are the basis for genetic linkage analysis and mapping disease-associated loci.