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Linkage analysis uses the co-inheritance of genetic markers with a disease locus to track disease alleles through families. It relies on the principle that loci close together on the same chromosome are less likely to be separated by recombination during meiosis.
- Recombination fraction (theta): The probability that a crossover occurs between two loci during meiosis. Ranges from 0 (completely linked) to 0.5 (unlinked/different chromosomes).
- LOD score: The log (base 10) of the odds ratio comparing linkage at a given theta versus no linkage (theta = 0.5). LOD >= 3 is evidence for linkage; LOD <= -2 excludes linkage.
- Informative meiosis: A meiosis where you can determine whether recombination occurred. Requires heterozygosity at the marker locus.
| LOD Score | Interpretation |
|---|---|
| >= 3.0 | Significant evidence for linkage (odds 1000:1) |
| 1.0 to 3.0 | Suggestive, not conclusive |
| -2.0 to 1.0 | Inconclusive |
| <= -2.0 | Linkage excluded at that theta |
- Indirect genetic testing: When the causative variant is unknown but linked markers are informative, linkage can be used for carrier detection or prenatal diagnosis
- Requires family structure: At least one affected individual and informative meioses
- Risk of error: If recombination occurs between marker and disease locus, the prediction is wrong. Error rate = recombination fraction.
- Requires informative family members (often multiple affected individuals)
- Cannot be used for de novo mutations
- Recombination between marker and disease locus leads to incorrect predictions
- Largely replaced by direct mutation testing but still used for some conditions where the causative variant is unidentifiable