Linkage Disequilibrium Notes

Linkage Disequilibrium

Mendel's Laws of Inheritance

Mendel's laws include:

  • Law of Segregation: During gamete formation, the two alleles for each gene (locus) separate, so each gamete carries only one allele for each gene (locus).
  • Law of Independent Assortment: Alleles for different traits segregate independently during gamete formation.
  • Law of Dominance: Some alleles are dominant, while others are recessive. An organism with at least one dominant allele will express the effect of the dominant allele.

Important Note: Mendel’s laws are NOT valid for multifactorial complex diseases.

Crossing Over/Homologous Recombination (HR)

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

Case 1: Distant Loci on the Same Homologous Chromosome

  • HR can happen during meiosis between SNP1 and SNP2, which are distant.
  • This generates new combinations of alleles:
    • Parental allele combination: (SNP1-A; SNP2-B) or (SNP1-a; SNP2-b)
    • Recombinant allele combination: (SNP1-A; SNP2-b) or (SNP1-a; SNP2-B)
  • Mendel’s law of independent segregation of alleles is respected.
    • SNP: Single Nucleotide Polymorphism

Case 2: Close Loci on the Same Homologous Chromosome

  • HR cannot happen during meiosis between SNP3 and SNP4 because they are too close to each other.
  • The gametes produced have the same allele combinations as the parental allele combination: (SNP3-E; SNP4-F) or (SNP3-e; SNP4-f).
  • There are NO recombinant allele combinations produced.
  • Mendel’s law of independent segregation of alleles is NOT respected.
  • The two SNPs are in Linkage Disequilibrium (LD): The alleles on one homolog are transmitted as a block to the offspring (Haplotype block).

Haplotype

  • A set of alleles at multiple loci located on the same homologous chromosome that tend to be inherited together from a single parent because of genetic linkage.
    • There is no homologous recombination/crossover between these alleles (too close to each other, so they are passed down through generations together).
    • Transmitted to offspring as a haplotype block across generations, leading to the persistence of an ancestral association.

Example:

Consider the following SNPs:

  • SNP1: A/G (Heterozygous)
  • SNP2: G/T (Heterozygous)
  • SNP3: T/C (Heterozygous)

If a child inherits the SNP1-A allele, then the child also inherits the SNP2-G allele and the SNP3-T allele located on the same chromosome.

  • Haplotype 1: AGT
  • Haplotype 2: GTC

Linkage Disequilibrium (LD)

  • LD simply means a non-random association of alleles at two or more loci on the same chromosome (influenced by distance between loci and evolutionary pressure).
    *100% LD between two loci means the alleles present on one homologous chromosome will be transmitted together to the offspring because no recombination can occur.
  • If LD>80% the two markers are still linked to a great extent and the presence of one allele at one loci. LD can be used to map chromosomal region associated with a disease trait / gene of interest -> GENETIC MARKERS

Consequence of Genetically Linked SNPs on Chronic Disease

Consider two haplotypes:

  • Haplotype 1: A, G, T
  • Haplotype 2: G, T, C

If SNP2 is associated with a trait linked to disease risk:

  • G allele: ↑ disease risk (e.g., ↓ enzyme activity) - risk allele
  • T allele: ↓ disease risk (e.g., 100% enzyme activity)

Then individuals of GG genotype for SNP2 will:

  • Have an ↑ disease risk
  • Also be homozygous AA for SNP1 and homozygous TT for SNP3 (act as genetic markers for risk allele G for SNP2).