Linkage Disequilibrium Notes

Linkage Disequilibrium

Mendel's Laws of Inheritance

  • Law of Segregation: During gamete formation, the two alleles for each gene (locus) separate, with each gamete carrying only one allele per gene.
  • Law of Independent Assortment: Alleles for different traits segregate independently during gamete formation.
  • Law of Dominance: Some alleles are dominant, others recessive; the dominant allele's effect is displayed if at least one is present.
  • Note: Mendel’s laws are not valid for multifactorial complex diseases.

Crossing Over/Homologous Recombination (HR)

  • Occurs during prophase I of meiosis where non-sister chromatids from homologous chromosomes exchange genetic material.
  • HR leads to new allele combinations (recombinant alleles).
  • Homologous chromosomes segregate in meiosis with each gamete receiving one homolog.
  • If two loci are very close, HR between them may occur, and the two loci will be transmitted as a block.

Case 1: Distant Loci on the Same Homologous Chromosome

  • HR can occur between distant SNPs (e.g., SNP1 and SNP2) during meiosis.
  • This generates new allele combinations:
    • Parental: (SNP1-A; SNP2-B) or (SNP1-a; SNP2-b)
    • Recombinant: (SNP1-A; SNP2-b) or (SNP1-a; SNP2-B)
  • Mendel’s law of independent segregation is respected.

Case 2: Close Loci on the Same Homologous Chromosome

  • HR cannot occur between very close SNPs (e.g., SNP3 and SNP4).
  • Gametes produced have the same allele combinations as the parental alleles: (SNP3-E; SNP4-F) or (SNP3-e; SNP4-f).
  • No recombinant allele combinations are produced.
  • Mendel’s law of independent segregation is NOT respected.
  • The two SNPs are in Linkage Disequilibrium (LD): alleles on one homolog are transmitted as a block to offspring (Haplotype block).

Haplotype

  • A set of alleles at multiple loci on the same homologous chromosome that tend to be inherited together due to genetic linkage.
    • No homologous recombination/crossover between these alleles (too close to each other).
    • Transmitted to offspring as a haplotype block across generations, maintaining ancestral associations.
  • Example:
    • SNP1: A/G (Heterozygous)
    • SNP2: G/T (Heterozygous)
    • SNP3: T/C (Heterozygous)
  • If a child inherits SNP1-A allele, they also inherit SNP2-G and SNP3-T alleles located on the same chromosome.

Linkage Disequilibrium (LD) Defined

  • LD is the non-random association of alleles at two or more loci on the same chromosome, influenced by distance and evolutionary pressure.
  • 100% LD means alleles on one homologous chromosome will be transmitted together because no recombination occurs.
  • If LD > 80%, the two markers are still highly linked; presence of one allele at one locus predicts the allele at the other.
  • LD can be used to map chromosomal regions associated with disease traits/genes of interest, acting as genetic markers.

Consequence of Genetically Linked SNPs on Chronic Disease

  • Example Haplotypes:
    • Haplotype 1: A, G, T
    • Haplotype 2: G, T, C
  • If SNP2 is associated with a disease trait:
    • G allele: ↑ disease risk (e.g., ↓ enzyme activity) - risk allele
    • T allele: ↓ disease risk (e.g., 100% enzyme activity)
  • Individuals with GG genotype for SNP2:
    • Have an ↑ disease risk
    • Will also likely be homozygous AA for SNP1 and homozygous TT for SNP3 (these act as genetic markers for the risk allele G at SNP2).