Single Nucleotide Polymorphisms

Single Nucleotide Polymorphisms - Tiny Changes, Big Impact

• Single Nucleotide Polymorphisms (SNPs): DNA sequence variations affecting a single nucleotide.
• Prevalence: Most common genetic variant; present in >1% of the population.
• Location: Found in coding (exons), non-coding (introns, regulatory), or intergenic regions.
  • Coding region SNP effects:
    • Synonymous (silent): Different codon, same amino acid.
    • Non-synonymous: Results in amino acid change.
      • Missense: Different amino acid.
      • Nonsense: Premature stop codon.
• Significance: Disease susceptibility, pharmacogenomics (drug response), population markers, forensics. within a DNA strand compared to a reference sequence)

⭐ SNPs are crucial for Genome-Wide Association Studies (GWAS), linking genetic variants to diseases and traits.

SNP Types & Effects - Code Breakers

• Coding SNPs (cSNPs): Impact protein.
  • Synonymous (Silent): No amino acid change; often benign.
  • Non-synonymous:
    • Missense: Alters one amino acid; variable effect.
    • Nonsense: Premature STOP codon; truncated, non-functional protein.
• Non-coding SNPs: Affect gene activity/splicing.
  • Regulatory: In promoters/enhancers; alter gene expression (↑/↓).
  • Intronic: Within introns; can disrupt mRNA splicing.
  • Intergenic: Between genes; may affect distant gene regulation.

Key Impacts:

• Disease risk (e.g., complex traits).
• Drug response variability (pharmacogenomics).
• Phenotypic differences.

⭐ > Non-synonymous SNPs are a major focus in identifying genetic causes of Mendelian diseases.

Finding SNPs - Genetic Detectives

SNP discovery identifies single base variations by comparing DNA sequences. Key steps involve sample preparation, data generation, and bioinformatic analysis.

• Primary Approaches:
  • DNA Sequencing:
    • Next-Generation Sequencing (NGS): WGS (Whole Genome) & WES (Whole Exome) for comprehensive, novel SNP discovery. Aligned to reference genome.
    • Sanger Sequencing: Gold-standard for targeted SNP validation.
  • Microarrays (SNP Chips):
    • High-throughput genotyping of thousands to millions of known SNPs.
    • Based on allele-specific oligonucleotide hybridization.
  • PCR-Based Methods:
    • For specific, known SNPs (e.g., RFLP, TaqMan assays, ARMS-PCR). Often used for validation or smaller scale studies.

⭐ GWAS (Genome-Wide Association Studies) heavily rely on SNP microarrays to find associations between SNPs and traits/diseases in large cohorts.

SNPs in Medicine - Clinical Clues

• Disease Susceptibility: SNPs can ↑ or ↓ risk for common diseases (e.g., diabetes, heart disease, autoimmune disorders).
  • APOE gene SNPs (ε2, ε3, ε4 alleles) and Alzheimer's disease risk.
    • ε4 allele: ↑ risk, earlier onset.
    • ε2 allele: protective effect.
• Pharmacogenomics: SNPs influence drug efficacy and adverse drug reactions (ADRs).
  • CYP2C19 SNPs: Clopidogrel metabolism (poor vs. extensive metabolizers).
  • VKORC1 SNPs: Warfarin sensitivity, dose adjustments.
  • TPMT SNPs: Azathioprine toxicity risk.
  • HLA-B5701*: Abacavir hypersensitivity.
• Cancer: Somatic SNPs in tumors (drivers/passengers); germline SNPs for predisposition (e.g., BRCA1/2 variants, though often not single SNPs).

⭐ Warfarin Dosing: SNPs in CYP2C9 (drug metabolism) and VKORC1 (drug target) genes are critical for determining appropriate warfarin dosage, significantly impacting anticoagulation therapy and reducing bleeding or clotting risks. This is a frequently tested pharmacogenomic application.

• Monogenic Diseases: While many SNPs are common, rare SNPs can be pathogenic and cause Mendelian disorders (e.g., Cystic Fibrosis - CFTR gene mutations, some of which are SNPs).
• Forensic Science: SNP profiling for individual identification (though less variable than STRs).

High‑Yield Points - ⚡ Biggest Takeaways

• SNPs: Most common genetic variation; single base-pair difference.
• Must be present in >1% of the population.
• Occur in coding (exons) or non-coding (introns, regulatory) regions.
• Impact disease susceptibility, drug metabolism (pharmacogenomics), and phenotypic traits.
• Non-synonymous SNPs alter protein sequence; synonymous SNPs do not.
• Crucial for GWAS, linkage disequilibrium (LD) analysis, and haplotype mapping.
• Detected via DNA microarrays and Next-Generation Sequencing (NGS).