The Use of Linked Markers in Genetic Disease

Question 1

Describe the basic principles of genetic linkage.

Answer 1

• Genetic linkage is the tendency for alleles at neighbouring loci to segregate together at meiosis.
• Therefore to be linked two loci must lie very close together.
• A group of alleles in a cluster at linked loci = a haplotype.
• Crossing over is more likely to occur between loci separated by some distance than those close together.

Question 2

Explain the difference between linkage equilibrium and disequilibrium in terms of recombination frequency.

Answer 2

• When recombination frequency (theta) ~ 0.5, there is no genetic linkage - i.e. equilibrium.
• Loci are far apart so independent assortment leads to half-half split between recombinant and non-recombinant DNA.
• When recombination frequency ~ 0, there is genetic linkage - i.e. linkage disequilibrium.
• There is no crossing over because loci are very close together.

Question 3

Define linkage disequilibrium.

Answer 3

Linkage disequilibrium - when two alleles are co-inherited more than would be expected by chance - i.e. the alleles are linked due to close proximity on the chromosome. These alleles are more likely to be inherited together than two alleles that are far apart.

Question 4

Explain how the frequency of recombination events is related to genetic distance, in mathematical terms.

Answer 4

• 1 centimorgan (cM) = the distance between 2 loci where 1% of the meiosis products are recombinant.
• 1 cM = 1 Mb = 1,000,000 base pairs.
• 2 or 3 recombination events per chromosome.
• E.g. recombination frequency = 20% - alleles are 20 cM apart = 20 Mb - but could be either direction?

Question 5

Explain how the LOD score predicts the probability of genetic linkage.

Answer 5

• Linkage measured by logarithim of odds (LOD) score.
• LOD > 3 - evidence of linkage, approximately equivalent to 1/1000 chance.
• LOD < -2 - evidence of no linkage.
• LOD between -1.9 and 2.9 - possible linkage.